DALLAS – July 03, 2025 – By using a genetic technique developed at UT Southwestern Medical Center that forces cells to rid themselves of mitochondria, researchers are gaining new insights into the function of these critical organelles. Their findings, published in Cell, add to fundamental knowledge about the role of mitochondria in cells and evolution and could eventually lead to new treatments for patients with mitochondrial diseases such as Leigh syndrome and Kearns-Sayre syndrome, which can affect numerous organ systems.

Jun Wu, Ph.D., is Associate Professor of Molecular Biology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. He is a Virginia Murchison Linthicum Scholar in Medical Research.

“Our new tool allows us to study how changes in mitochondrial abundance and the mitochondrial genome affect cells and organisms,” said Jun Wu, Ph.D., Associate Professor of Molecular Biology at UT Southwestern. Dr. Wu co-led the study with Daniel Schmitz, Ph.D., a former graduate student in the Wu Lab who is now a postdoctoral fellow at the University of California, Berkeley.

Mitochondria are organelles found in the cells of most eukaryotic organisms, including animals, plants, and fungi, whose cells contain a membrane-bound nucleus and other membrane-bound organelles. They have their own genetic material, passed down exclusively through females of a species. Mitochondria are thought to have originated as prokaryotic cells – which lack membrane-bound organelles – and to have invaded ancestral eukaryotic cells and formed a symbiotic relationship with them.

Researchers have long known that these organelles serve as cells’ powerhouses, generating the energetic molecule adenosine triphosphate that fuels all cellular operations. However, recent studies have shown mitochondria play direct roles in regulating cell death, differentiating stem cells into other cell types, transmitting molecular signals, aging, and developmental timing.

Although mitochondria appear to perform many of these roles through “crosstalk” with the DNA in a cell’s nucleus, how they perform this function – and what happens if this crosstalk ceases – has been unknown.

Daniel Schmitz, Ph.D., is a former graduate student in the Wu Lab at UT Southwestern.

To help answer these questions, Dr. Wu, Dr. Schmitz, and their colleagues took advantage of a pathway called mitophagy that cells normally use to dispose of old or damaged mitochondria. Using genetic engineering, the researchers forced cells to degrade all their mitochondria – a process known as “enforced mitophagy.”

The researchers used this process on human pluripotent stem cells (hPSCs), a type of cell typically formed early in development that can differentiate into other cell types. Although this alteration caused the cells to stop dividing, the researchers unexpectedly found that the mitochondria-depleted cells could survive in petri dishes up to five days. They had similar results with different types of mouse stem cells and hPSCs harboring a pathogenic mitochondrial DNA mutation, suggesting enforced mitophagy can be a viable tool for depleting mitochondria across species and cell types.

To determine how removing mitochondria affected the hPSCs, the researchers assessed nuclear gene expression. They found that 788 genes became less active and 1,696 became more active. An analysis of the affected genes showed the hPSCs appeared to retain their ability to form other cell types and that they could partially compensate for the lack of mitochondria, with proteins encoded by nuclear genes taking over energy production and certain other functions typically performed by the missing organelles.

Then the researchers, in an attempt to better understand crosstalk between mitochondria and the cell nucleus, fused hPSCs with pluripotent stem cells (PSCs) from humans’ closest primate relatives – including chimpanzee, bonobo, gorilla, and orangutan. This formed “composite” cells with two nuclear genomes and two sets of mitochondria, one from each species. These composite cells selectively removed all non-human primate mitochondria, leaving behind only human mitochondria.

Next, using enforced mitophagy, the scientists created hPSCs devoid of human mitochondria and fused them to non-human primate PSCs, again creating cells carrying nuclear genomes from both species, but this time only non-human mitochondria. An analysis of composite cells containing either human or non-human mitochondria showed that the mitochondria were largely interchangeable despite millions of years of evolutionary separation, causing only subtle differences in gene expression within the composite nucleus.

Interestingly, the genes that differed in activity among cells harboring human and non-human mitochondria were mostly linked to brain development or neurological diseases. This raises the possibility that mitochondria may play a role in the brain differences between humans and our closest primate relatives. However, Dr. Wu said, more research – especially studies comparing neurons made from these composite PSCs – will be needed to better understand these differences.

Finally, the researchers studied how depleting mitochondria might affect development in whole organisms. They used a genetically encoded version of enforced mitophagy to reduce the amount of mitochondria in mouse embryos, then implanted them into surrogate mothers to develop. Embryos missing more than 65% of their mitochondria failed to implant in their surrogate’s uterus. However, those missing about a third of their mitochondria experienced delayed development, catching up to normal mitochondrial numbers and a typical developmental timeline by 12.5 days after fertilization.

Together, the researchers say, these results serve as starting points for new lines of research into the different roles mitochondria play in cellular function, tissues and organ development, aging, and species evolution. They plan to use enforced mitophagy to continue studying these organelles in a variety of capacities.

Other UTSW researchers who contributed to this study are Peter Ly, Ph.D., Assistant Professor of Pathology and Cell Biology; Daiji Okamura, Ph.D., Visiting Assistant Professor of Molecular Biology; Seiya Oura, Ph.D., and Leijie Li, Ph.D., postdoctoral researchers; Yi Ding, Ph.D., Research Associate; Rashmi Dahiya, Ph.D., Senior Research Associate; Emily Ballard, B.S., graduate student researcher; and Masahiro Sakurai, Ph.D., Research Scientist.

Dr. Wu is a Virginia Murchison Linthicum Scholar in Medical Research. Drs. Wu and Ly are members of the Harold C. Simmons Comprehensive Cancer Center.

About UT Southwestern Medical Center 

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 140,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5.1 million outpatient visits a year.

DALLAS – July 02, 2025 – Adding targeted radiation to chemotherapy prior to surgery may offer better control of pancreatic tumors – potentially reducing the rate of recurrence after treatment, according to a new study from UT Southwestern Medical Center. Published in Clinical Cancer Research, the novel study offers evidence of a more effective approach with biological insights for treating one of the most aggressive and lethal forms of cancer.

Todd Aguilera, M.D., Ph.D., is Assistant Professor of Radiation Oncology and a member of the Experimental Therapeutics Research Program at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

“Pancreatic ductal adenocarcinoma (PDAC) is extremely difficult to treat because even after chemotherapy and surgery, tumors often grow back, many times at the original site,” said study leader Todd Aguilera, M.D., Ph.D., Assistant Professor of Radiation Oncology and a member of the Experimental Therapeutics Research Program at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. “Our findings suggest stereotactic ablative radiotherapy (SAbR), which delivers high-dose radiation with minimal toxicity, may improve clinical outcomes for patients with PDAC by lowering the risk of recurrence – especially in cancers that invade or encase major arteries.”

The retrospective study compared 181 patients who were treated for pancreatic cancer at UT Southwestern and Parkland Health between 2012 and 2023 using neoadjuvant chemotherapy – designed to shrink the tumor prior to surgery – and either received or didn’t receive SAbR. Using RNA sequencing, the researchers examined molecular changes in tumor tissue among 43 of those patients to understand the biological effects of SAbR. 

Despite having more advanced disease at the outset, patients treated with SAbR had better treatment response and notably improved local control, or prevention of recurrence at the original site – particularly when arterial involvement was present — but similar overall survival rates. “This matters because local tumor regrowth causes significant suffering for patients,” Dr. Aguilera said. “As systemic therapies continue to improve, the burden of local recurrence becomes even more prominent – and more important to address.” 

The researchers, including first author and M.D./Ph.D. student researcher Peter Q. Leung, also found evidence that SAbR stimulated the immune system, increasing cancer-fighting lymphocytes in SAbR-treated tumors.

UT Southwestern M.D./Ph.D. student researcher Peter Q. Leung is the study's first author.

“While further study is needed, it’s possible that there is potential in combining high-dose ablative radiation with immunotherapies,” Dr. Aguilera said. “That could open up new areas to enhance antitumor immunity and ultimately improve cure rates for pancreatic patients, which today stand only at around 30% for those who undergo surgery.”

The research builds upon previous studies conducted in the Aguilera Lab, which focus on understanding how radiation changes the tumor microenvironment. 

“With high-resolution tools like single-cell RNA sequencing and multiplexed immunofluorescence, we are now investigating how each patient’s tumor responds at the cellular and molecular level and using that insight to develop smarter, more targeted treatments,” Dr. Aguilera said. “Detailed tissue analyses like those conducted here at UT Southwestern are critical for uncovering new therapeutic directions. This kind of work is only possible at a center like ours, where an interdisciplinary team collaborates closely to tailor the right treatment path for each patient. It also depends on the incredible commitment of our patients, who empower us to learn from every case. And none of it happens without dedicated trainees like Mr. Leung and the rest of our team, who take on critical parts of the effort.”

Dr. Aguilera is a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research, a National Cancer Institute (NCI) Cancer Moonshot Scholar, and a Damon Runyon Clinical Investigator.  

Other UTSW researchers who contributed to the study are Herbert J. Zeh III, M.D., Chair and Professor of Surgery; Adam C. Yopp, M.D., Professor of Surgery and Chief of the Division of Surgical Oncology; John C. Mansour, M.D., Professor of Surgery; Song Zhang, Ph.D., Professor in the Peter O’Donnell Jr. School of Public Health; Cheryl M. Lewis, Ph.D., Associate Professor in the Simmons Cancer Center and of Pathology; Patricio M. Polanco, M.D., Associate Professor of Surgery, Director of Robotic Surgery Training, co-Director of the Pancreatic Cancer Program, and co-Director of the Pancreatic Cancer Prevention Clinic; Nina N. Sanford, M.D., Associate Professor of Radiation Oncology and Chief of Gastrointestinal Radiation Oncology Service; Syed Kazmi, M.D., Associate Professor of Internal Medicine in the Division of Hematology and Oncology; Matthew R. Porembka, M.D., Associate Professor of Surgery; Megan Wachsmann, M.D., Assistant Professor of Pathology; Zhikai Chi, M.D., Ph.D., Assistant Professor of Pathology; Salwan Al Mutar, M.D., Assistant Professor of Internal Medicine in the Division of Hematology and Oncology; David Hsieh, M.D., Assistant Professor of Internal Medicine in the Division of Hematology and Oncology; Eslam A. Elghonaimy, Ph.D., Instructor of Radiation Oncology; Muhammad S. Beg, M.D., Adjunct Associate Professor of Internal Medicine in the Division of Hematology and Oncology; Ahmed M. Elamir, M.D., Clinical Fellow in Radiation Oncology; Neha Barrows, B.S., Research Assistant II in Radiation Oncology; Hollis Notgrass, M.S., Lead Pathologist Assistant; Ethan Johnson, Clinical Research Coordinator; Cassandra Hamilton, B.S., Senior Regulatory Analyst; and Samy Castillo-Flores, M.D., and Ricardo E. Nunez Rocha, M.D., postdoctoral researchers.

Drs. Zeh, Yopp, Mansour, Zhang, Lewis, Polanco, Sanford, Kazmi, Porembka, Wachsmann, Chi, Al Mutar, and Hsieh are all members of Simmons Cancer Center.   

The study was funded by a Simmons Cancer Center Translational Cancer Research Pilot Grant; CPRIT (RR170051); the Carroll Shelby Foundation; the UT Southwestern Disease Oriented Scholars Program; and an NCI Cancer Center Support Grant (P30CA142543).

About UT Southwestern Medical Center 

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 140,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5.1 million outpatient visits a year.

About Parkland Health

Parkland Health is one of the largest public hospital systems in the country. Premier services at the state-of-the-art Parkland Memorial Hospital include the Level I Rees-Jones Trauma Center, the only burn center in North Texas verified by the American Burn Association for adult and pediatric patients, and a Level III Neonatal Intensive Care Unit. The system also includes two on-campus outpatient clinics – the Ron J. Anderson, MD Clinic and the Moody Outpatient Center, as well as more than 30 community-based clinics and numerous outreach and education programs. By cultivating its diversity, inclusion, and health equity efforts, Parkland enriches the health and wellness of the communities it serves. For more information, visit parklandhealth.org.

DALLAS – June 23, 2025 – Using gene editing in a preclinical model, researchers at UT Southwestern Medical Center blocked the symptoms of a rare smooth muscle disease before they developed. Their findings, published in Circulation, could eventually lead to gene therapies for this and other genetic diseases affecting smooth muscle cells.

Eric Olson, Ph.D., is Chair and Professor of Molecular Biology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. Dr. Olson holds The Robert A. Welch Distinguished Chair in Science, the Pogue Distinguished Chair in Research on Cardiac Birth Defects, and the Annie and Willie Nelson Professorship in Stem Cell Research.

“Gene editing has been used in other disease contexts, but its application to inherited vascular diseases, particularly targeting smooth muscle cells in vivo, is still emerging. Our approach advances the field by demonstrating functional correction in a cell type that’s notoriously difficult to target,” said Eric Olson, Ph.D., Chair and Professor of Molecular Biology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. Dr. Olson co-led the study with Ning Liu, Ph.D., Professor of Molecular Biology, and first author Qianqian Ding, Ph.D., postdoctoral researcher, both members of the Olson Lab.

Fewer than 1,000 people in the U.S. have multisystem smooth muscle dysfunction syndrome (MSMDS). This disease is marked by widespread disorders in smooth muscles, a type of non-striated contractile tissue found in blood vessels and various hollow organs.

Patients with MSMDS develop problems affecting the lungs, gastrointestinal system, kidneys, bladder, and eyes beginning in childhood. They are also significantly more vulnerable to aortic aneurysms and aortic dissections – medical emergencies affecting the body’s largest artery that necessitate emergency surgery to prevent sudden death.

Because MSMDS is often caused by a single nucleotide mutation – a pathological change in one “letter” of the genetic code, in this case in a gene called ACTA2 – gene therapy could theoretically cure patients with this disease, Dr. Ding explained. However, no gene therapies developed thus far have successfully targeted smooth muscle tissues.

Ning Liu, Ph.D., is Professor of Molecular Biology at UT Southwestern.

To look for a possible solution, Drs. Ding, Liu, and Olson and their colleagues used a strategy called base editing – a variation of the CRISPR gene editing method that uses targeted molecular machinery to swap one specific letter of the genetic code for another, converting a mutant gene to its healthy form. The researchers tested this approach first in human smooth muscle cells carrying mutant ACTA2. After introducing the base editing components into mutant cells growing in petri dishes, the scientists showed that the disease-causing mutant version of ACTA2 was corrected. This treatment resolved pathological traits seen in the mutant cells, including an inability to contract and excessive proliferation and migration.

While this gene editing strategy appeared to be successful in cells, Dr. Ding explained, applying it in whole organisms was far more challenging because the base editing machinery must be expressed specifically in smooth muscle cells. To achieve this, they packaged them with a promoter – a DNA fragment that ensures genes are expressed in the right cell type. Mice carrying the human ACTA2 mutation responsible for MSMDS that received the base editing components three days after birth remained healthy, while untreated mice developed symptoms including enlarged bladders and kidneys, dilated small intestines, and weakened aortas.

This strategy might be effective in human patients early in their disease process – an approach the team hopes will eventually be tested in clinical trials. They plan to investigate in future studies whether gene editing could reverse symptoms of MSMDS after they’ve developed and whether their approach could hold promise for other genetic smooth muscle diseases.

First author Qianqian Ding, Ph.D., is a postdoctoral researcher in the Olson Lab at UT Southwestern.

Other UTSW researchers who contributed to this study are Lin Xu, Ph.D., Assistant Professor in the Peter O’Donnell Jr. School of Public Health and of Pediatrics; Hui Li, Ph.D., and John McAnally, B.S., Senior Research Scientists; Lei Guo, Ph.D., Computational Biologist; Camryn MacDonald, B.S.A., Research Assistant; Wei Tan, M.D., and Efrain Sanchez-Ortiz, Ph.D., Research Scientists; and Peiheng Gan, Ph.D., M.B.B.S., and Zhisheng Xu, Ph.D., postdoctoral researchers.

Dr. Olson, Director of the Hamon Center for Regenerative Science and Medicine, holds The Robert A. Welch Distinguished Chair in Science, the Pogue Distinguished Chair in Research on Cardiac Birth Defects, and the Annie and Willie Nelson Professorship in Stem Cell Research.

This study was funded by grants from the National Institutes of Health (R01HL130253, R01HL157281, P50HD087351), The Welch Foundation (1-0025), The Leducq Foundation Transatlantic Networks of Excellence, the British Heart Foundation’s Big Beat Challenge award to CureHeart (BBC/F/21/220106), and the American Heart Association (25POST1372779).

About UT Southwestern Medical Center 

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 140,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5.1 million outpatient visits a year.

DALLAS – June 18, 2025 – A gene-editing delivery system developed by UT Southwestern Medical Center researchers simultaneously targeted the liver and lungs of a preclinical model of a rare genetic disease known as alpha-1 antitrypsin deficiency (AATD), significantly improving symptoms for months after a single treatment, a new study shows. The findings, published in Nature Biotechnology, could lead to new therapies for a variety of genetic diseases that affect multiple organs.

Daniel Siegwart, Ph.D., is Professor of Biomedical Engineering, Biochemistry, and in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. He holds the W. Ray Wallace Distinguished Chair in Molecular Oncology Research.

“Multi-organ diseases may need to be treated in more than one place. The development of multi-organ-targeted therapeutics opens the door to realizing those opportunities for this and other diseases,” said study leader Daniel Siegwart, Ph.D., Professor of Biomedical Engineering, Biochemistry, and in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

Gene editing – a group of technologies designed to correct disease-causing mutations in the genome – has the potential to revolutionize medicine, Dr. Siegwart explained. Targeting these technologies to specific organs, tissues, or cell populations will be necessary to effectively and safely treat patients.

In 2020, the Siegwart Lab reported a new approach called Selective Organ Targeting, or SORT, which uses specific components in the lipid nanoparticles (LNPs) that encapsulate gene-editing molecules to target certain organs. Although the researchers have demonstrated that SORT can edit genes selectively in specific organs, such as the liver, lungs, and spleen, the team had yet to demonstrate that this system could target multiple organs simultaneously.

Genetic therapies aimed at more than one organ will be critical to treat diseases like AATD, in which a mutation that affects a single nucleotide – one “letter” in the genetic code – causes buildup of a toxic protein in the liver. Because the healthy version of this protein also plays a role in inhibiting an enzyme that breaks down a key protein in the lungs, AATD patients’ lungs are also affected, leading to a form of emphysema.

To correct the causative mutation in both organs simultaneously, Dr. Siegwart and his colleagues re-engineered the SORT nanoparticles to carry large gene-editing proteins necessary to replace the single affected nucleotide with a healthy one. They also developed new formulas for the liver- and lung-targeting nanoparticles, changing their ingredients to more efficiently reach these organs.

Tests in liver cells derived from patients showed these new nanoparticles effectively edited the mutated gene, known as SERPINA1. In a mouse model of AATD that carries the mutated human gene in each cell, a single dose of the liver- and lung-targeting SORT nanoparticles resulted in gene editing of about 40% of liver cells and about 10% of AT2 lung cells – those primarily affected by AATD. Evaluation of liver cells showed that editing remained stable in this organ for at least 32 weeks, reducing levels of the mutated protein by 80%.

Within four weeks of this treatment, aggregates of the toxic protein in the liver had faded away. Although this mouse model doesn’t develop the same lung pathology as human patients, the researchers found that the damaging lung enzyme left unchecked in AATD was inhibited by 89%.

Together, Dr. Siegwart said, these results show that SORT can be used to treat multi-organ diseases. He and his colleagues continue to develop SORT into clinical therapies for various diseases through ReCode Therapeutics, which has licensed intellectual property from UT Southwestern. Dr. Siegwart is a co-founder and member of the scientific advisory board of the company. He has financial interests in ReCode Therapeutics, Signify Bio, and Jumble Therapeutics.

Other UTSW researchers who contributed to this study are first author Minjeong Kim, Ph.D., postdoctoral researcher; Sumanta Chatterjee, Ph.D., Instructor of Biomedical Engineering; Eunice S. Song, B.S., Yehui Sun, M.S., and Shiying Wu, B.S., graduate student researchers; Sang M. Lee, Ph.D., postdoctoral researcher; Priyanka Patel, M.Sc., Research Associate; and Zeru Tian, Ph.D., Research Scientist.

Dr. Siegwart holds the W. Ray Wallace Distinguished Chair in Molecular Oncology Research.

This study was funded by a Sponsored Research Agreement with ReCode Therapeutics and a grant from the National Institutes of Health National Institute of Biomedical Imaging and Bioengineering (R01 EB025192-01A1).

About UT Southwestern Medical Center 

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 140,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5.1 million outpatient visits a year.

Nagesh Peddada, Ph.D., is Assistant Professor in the Center for the Genetics of Host Defense and of Immunology at UT Southwestern.

“Seeing the structure of midnolin lends insight on how this protein helps cells dispose of other unneeded proteins in a way that’s different from the classical mechanism we’re used to seeing – a process that could have significant implications for cancer and immune-related diseases,” said Nagesh Peddada, Ph.D., Assistant Professor in the Center for the Genetics of Host Defense and of Immunology at UT Southwestern. He co-led the study with Bruce Beutler, M.D., Director of the Center for the Genetics of Host Defense and Professor of Immunology and Internal Medicine.

Dr. Beutler, who shared the 2011 Nobel Prize in Physiology or Medicine for his discovery of an important family of receptors found on immune cells, has long used mutagenesis – a method for introducing mutations into the genes of animal models – as a key approach for discovering the function of genes. Recently, the Beutler Lab pioneered a method known as automated meiotic mapping (AMM) that links abnormal traits in mutant mice to the mutations that cause them, thereby identifying genes needed to maintain a normal physiologic state.

Bruce Beutler, M.D., is Director of the Center for the Genetics of Host Defense and Professor of Immunology and Internal Medicine at UT Southwestern. Dr. Beutler, a Nobel Laureate and a Regental Professor, holds the Raymond and Ellen Willie Distinguished Chair in Cancer Research, in Honor of Laverne and Raymond Willie, Sr. He is also a member of the Harold C. Simmons Comprehensive Cancer Center.

Combining these tools, he and his colleagues reported last year that mutations in Midn, the gene that produces midnolin, protected mice genetically predisposed to developing B-cell leukemias and lymphomas. B cells, which are critical components of the adaptive immune system, divide out of control in these types of cancer. Using genetic tricks to eliminate or drastically reduce midnolin production significantly extended the affected animals’ lifespans by preventing them from developing these diseases at all.

Further experiments revealed that midnolin’s role in B cells is to ferry proteins to proteasomes, cellular organelles that degrade proteins that are damaged or no longer useful to the cell. Midnolin also stimulates proteasome activity, increasing the rate at which damaged proteins are removed from cells. Nearly all proteins routed to proteasomes are tagged for disposal by another protein called ubiquitin. However, proteins carried by midnolin aren’t tagged with ubiquitin, Dr. Peddada explained. How midnolin functions without ubiquitin’s help has been unclear.

Using UTSW’s Cryo-Electron Microscopy Facility, the researchers obtained three-dimensional images of midnolin bound to proteasomes at nearly atomic-level resolution. These images revealed key portions of midnolin that are critical for its partnership with proteasomes. One of these portions has a shape similar to ubiquitin that allows midnolin to open the same gateway in proteasomes that proteins must cross for their disposal.

Some therapies for B-cell leukemias and lymphomas work by inhibiting proteasome activity, Dr. Beutler explained. However, proteasome inhibitors come with a host of side effects, including gastrointestinal problems, decreased platelets that pose a bleeding risk, and nerve damage. Because midnolin is found primarily in B cells, developing drugs that block any of its actions could offer a safer alternative to proteasome inhibitors – a topic that the Beutler Lab plans to investigate in the future.

This image shows the structure of a 26S proteasome (in tan and grey). A protein called midnolin (red) helps deliver unwanted proteins to the proteasome and connects with two key parts — RPN1 (blue) and RPN11 (green). This setup helps guide the unwanted protein to the right spot so the proteasome can break it down and keep the cell healthy.

Other UTSW researchers who contributed to this study include Xiaochen Bai, Ph.D., Associate Professor of Biophysics and Cell Biology; Xue Zhong, Ph.D., Jin Huk Choi, Ph.D., and Eva Maria Y. Moresco, Ph.D., Assistant Professors in the Center for the Genetics of Host Defense and of Immunology; Yan Yin, Ph.D., Research Scientist; Danielle Renee Lazaro, B.S., Research Technician II; Jianhui Wang, M.S., Senior Research Scientist; and Stephen Lyon, M.A., Computational Research Scientist.

Dr. Beutler, a Regental Professor, holds the Raymond and Ellen Willie Distinguished Chair in Cancer Research, in Honor of Laverne and Raymond Willie, Sr. He is also a member of the Cellular Networks in Cancer Research Program in the Harold C. Simmons Comprehensive Cancer Center at UTSW.

This research was funded by grants from the National Institutes of Health (R01AI125581) and The Welch Foundation (I-1944).

About UT Southwestern Medical Center 

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 140,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5.1 million outpatient visits a year.

DALLAS – June 04, 2025 – A genetic mutation that fuses two genes drives several different cancer types by forming networks of protein interactions that alter gene expression in cells, a study by UT Southwestern Medical Center researchers suggests. The findings, published in Cell, could lead to new treatments for an aggressive kidney cancer and may hold promise for a diverse set of other cancers, the study authors said.

“This research identifies a common molecular mechanism shared across diverse cancer-driving oncofusions, revealing a potentially druggable vulnerability,” said Benjamin Sabari, Ph.D., Assistant Professor in the Cecil H. and Ida Green Center for Reproductive Biology Sciences and member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. Dr. Sabari co-led the study with first authors Heankel Lyons, Ph.D., a former member of the Sabari Lab who is now a postdoctoral researcher at Stanford University, and Prashant Pradhan, Ph.D., a postdoctoral researcher at UTSW.

Benjamin Sabari, Ph.D., is Assistant Professor in the Cecil H. and Ida Green Center for Reproductive Biology Sciences and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

Mutations involving fusions of genes, known as chromosomal translocations, are relatively common in cancers; the different hybrid proteins that they produce, known as oncofusions, are thought to play roles in about 17% of malignancies, Dr. Sabari explained. Why fusing different portions of proteins together causes cancer is understood for a few cancers, but it is unclear for others. These include translocation renal cell carcinoma (tRCC), an aggressive cancer subtype that affects about 4% of adults with renal cell carcinoma and is the most common renal cell carcinoma subtype in children.

About two-thirds of tRCC cases are thought to be caused by fusion of the gene that codes for the transcription factor TFE3 (a protein that’s key for activating specific genes) with one of three other genes: PRCC, ASPL, or SFPQ. Because the three genes seemingly have nothing in common, Dr. Sabari said, why TFE3 fuses with these specific partners and how this fusion confers malignancy was unknown.

To answer these questions, Drs. Sabari, Lyons, and Pradhan and their colleagues examined tRCC cells from patients treated in UTSW’s Kidney Cancer Program, kept in a biorepository led by study co-author James Brugarolas, M.D., Ph.D., Professor of Internal Medicine and the program’s Director. Using a special stain, they saw that the oncofusion proteins formed biomolecular condensates – dynamic networks of different proteins that segregate themselves within cells – but the “wild-type” (not mutated) TFE3 protein did not. These results suggest that a common feature of the seemingly random fusion partners is the ability to form condensates.

Previous work from the Sabari Lab has shown that condensates can regulate transcription – the process that copies the genetic information in DNA into RNA, an initial step for producing proteins from genes – by selectively capturing key regulatory proteins at target genes. This finding led the researchers to investigate whether oncofusion condensates selectively captured common proteins. When the researchers mixed material extracted from cell nuclei with oncofusion proteins produced by the TFE3 translocation, the proteins readily formed biomolecular condensates, confirming that these hybrid proteins spur condensate formation. Examining proteins enmeshed in the oncofusion condensates identified RNA polymerase II, an enzyme responsible for transcription.

How these three different oncofusions were all able to capture RNA polymerase II was unclear until the researchers compared the amino acid building blocks that make up normal or wild-type TFE3 with those that make up the three mutated oncofusion versions. They found that the mutated versions contained a higher proportion of amino acids that can chemically interact with RNA polymerase II. Upon swapping amino acids between wild-type TFE3 and the TFE3 oncofusion, the oncofusions lost their ability to interact with RNA polymerase II, whereas, conversely, wild-type TFE3 gained the ability to interact with RNA polymerase II, thus confirming the central role of the identified amino acid mixtures in capturing RNA polymerase II and in driving the process of gene transcription.

Cells carrying wild-type TFE3 engineered to carry more of the amino acids from the mutant version adopted cancerous behaviors, becoming more proliferative, invasive, and migratory. The most likely explanation is that RNA polymerase II bound by the mutant amino acids prompted the expression of genes that cause this malignant activity, said Dr. Sabari, also Assistant Professor of Molecular Biology and Obstetrics and Gynecology.

Curious about whether this mechanism might apply to other cancers, the research team combed through a database of known oncofusion mutations found in a variety of cancer types. By examining the amino acids that these mutations code for, the researchers saw combinations similar to those found in mutated TFE3 and found that these other oncofusions also captured RNA polymerase II. These findings suggest that these other oncofusions might be driving diverse cancers through a similar molecular mechanism observed for tRCC.

Finding a way to disrupt these interactions could offer a new way to treat these cancers – a topic that the Sabari Lab plans to pursue in the future.

Dr. Brugarolas holds the Sherry Wigley Crow Cancer Research Endowed Chair in Honor of Robert Lewis Kirby, M.D. He is Principal Investigator of the Kidney Cancer SPORE P50CA196516 grant from the National Cancer Institute (NCI).

Other UTSW researchers who contributed to this study are Prasad R. Koduru, Ph.D., Professor of Pathology; Chao Xing, Ph.D., Professor in the Eugene McDermott Center for Human Growth and Development, the Lyda Hill Department of Bioinformatics, and the Peter O’Donnell Jr. School of Public Health; Payal Kapur, M.D., Professor of Pathology and Urology; Gopinath Prakasam, Ph.D., Assistant Instructor of Internal Medicine; Kathleen McGlynn, M.S., Senior Research Associate; Vanina T. Tcheuyap, M.S., Research Associate; Ze Yu, M.S., and Dinesh Ravindra Raju, M.S., Computational Biologists; Shubham Vashishtha, Ph.D., and Xiang Li, Ph.D., postdoctoral researchers; and Mikayla Eppert, B.S., graduate student researcher.

Drs. Brugarolas, Kapur, Koduru, and Xing are members of the Simmons Cancer Center.

The research was funded by grants from the Cancer Prevention and Research Institute of Texas (RR190090), The Welch Foundation (I-2163-20230405 and V-I-0004-20230731), and the National Institutes of Health through the National Institute of General Medical Sciences (GM147583) and the National Cancer Institute through the Kidney Cancer SPORE (P50CA196516) and Cancer Center Support Grant (P30CA142543).

About UT Southwestern Medical Center 

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 140,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5.1 million outpatient visits a year.

DALLAS – May 20, 2025 – Zhijian “James” Chen, Ph.D., Professor of Molecular Biology and Director of the Center for Inflammation Research at UT Southwestern Medical Center, has been elected to the Fellowship of the Royal Society, the United Kingdom’s national academy of sciences and the oldest scientific academy in continuous existence.  

One of the world’s leading experts on innate immunity, Dr. Chen has been recognized with numerous honors for his research, including the 2024 Albert Lasker Basic Medical Research Award and the 2019 Breakthrough Prize in Life Sciences. He has also been elected to both the U.S. National Academy of Sciences and U.S. National Academy of Medicine.

“Dr. Chen’s breakthroughs have significantly advanced the field of immunology, paving the way for new approaches to the development of more effective vaccines and novel therapies for a broad range of diseases, including cancer and autoimmune disorders,” said Daniel K. Podolsky, M.D., President of UT Southwestern. “His election to the Royal Society reflects the vast impact of his discoveries, and UT Southwestern takes great pride in seeing Dr. Chen’s work recognized by this high honor.”

Innate immunity is the body’s first response to pathogens, allowing rapid response when these foreign agents attack and destroy cells and tissues. The Chen Lab is broadly interested in mechanisms of signal transduction – the mechanisms by which cells communicate with their surroundings and detect harmful or foreign insults.

Dr. Chen’s discoveries include the identification of MAVS, the first mitochondrial protein known to be involved in immunity against infections. In 2012, he identified cGAS (cyclic GMP-AMP synthase), which senses foreign DNA in a cell’s interior, or cytoplasm. It then activates STING (stimulator of interferon genes) and triggers an inflammatory response, including the production of type 1 interferons, essential for combating infections and regulating immune responses.

“I am deeply honored and humbled to be elected to the Royal Society. I look forward to the incredible moment when I will have the opportunity to sign the same book that has been signed by Isaac Newton, Charles Darwin, Albert Einstein, and other eminent scientists, including our own Mike Brown and Joe Goldstein. This recognition by the Royal Society reflects the impact of discoveries made through the dedication and talent of the scientists and trainees in my lab, and the potential of our work in improving human health,” said Dr. Chen, who is also a Howard Hughes Medical Institute Investigator and member of the Center for the Genetics of Host Defense and the Harold C. Simmons Comprehensive Cancer Center at UTSW.

Founded in 1660, the Royal Society’s Fellowship includes many of the world’s most eminent scientists, engineers, and technologists. At UT Southwestern, Nobel Laureates Michael S. Brown, M.D., Professor of Molecular Genetics, and Joseph L. Goldstein, M.D., Chair and Professor of Molecular Genetics, are Foreign Members of the Royal Society.

Dr. Chen is also a recipient of the Paul Ehrlich and Ludwig Darmstaedter Prize, Germany’s highest honor in the field of medicine (2025), the Louisa Gross Horwitz Prize (2023), the William B. Coley Award for Distinguished Research in Basic and Tumor Immunology (2020), the Switzer Prize (2019), the Lurie Prize in Biomedical Sciences (2018), and the National Academy of Sciences Award in Molecular Biology (2012).

Dr. Chen holds the George L. MacGregor Distinguished Chair in Biomedical Science. Dr. Podolsky holds the Philip O’Bryan Montgomery, Jr., M.D. Distinguished Presidential Chair in Academic Administration and the Charles Cameron Sprague Distinguished Chair in Biomedical Science. Dr. Brown, a Regental Professor, holds The W.A. (Monty) Moncrief Distinguished Chair in Cholesterol and Arteriosclerosis Research, and the Paul J. Thomas Chair in Medicine. Dr. Goldstein, a Regental Professor, holds the Julie and Louis A. Beecherl, Jr. Distinguished Chair in Biomedical Research, and the Paul J. Thomas Chair in Medicine.

About UT Southwestern Medical Center   

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 140,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5.1 million outpatient visits a year.

FORT WORTH – May 12, 2025 – Ushering in a new era of cancer care in Fort Worth, UT Southwestern Medical Center broke ground today on a $177 million Radiation Oncology campus that will provide the most advanced therapies for patients of the nation’s 12th-largest city.

The 65,000-square-foot facility, which will include the city’s first MRI-guided precision radiation treatment, is expected to meet the growing demands for cancer care in Fort Worth and the surrounding area for decades to come. The campus is projected to open in 2028 and will be connected to UT Southwestern’s Moncrief Cancer Institute in the city’s Medical District.

“This milestone, once completed, will ensure that Tarrant County residents have access to the best available cancer care, combining the latest advances in medical technology with the expertise of our clinicians and researchers, who are some of the top cancer specialists in the country,” said Daniel K. Podolsky, M.D., President of UT Southwestern. 

“Fort Worth is one of the fastest-growing cities in the country, and our high quality of life is a major driver of that growth,” Fort Worth Mayor Mattie Parker said. “To continue to meet this moment, we need world-class health and cancer care. We know UT Southwestern is at the center of that.”

A generous lead gift from esteemed philanthropists Sherri and Robert “Bobby” L. Patton Jr. is helping to make the new expansion possible. Their support underscores the vital role of private philanthropy in advancing UT Southwestern’s impact and ensuring that patients across the region have access to the most cutting-edge radiation oncology services close to home.

“Fort Worth is one of the greatest cities in America. It should have great cancer care. This expansion will bring cutting-edge technology and vital health care to our community,” Sherri Patton said.

As many as two-thirds of cancer patients need radiation therapy, and the UT Southwestern expansion will create the largest radiation oncology facility in the Fort Worth area, broadening access for patients of all oncologists and offering a convenient location close to home for patients living in Fort Worth and the surrounding area, who often require regular or daily trips for this lifesaving treatment.

The new facility will feature:

• Four linear accelerators (LINACs) to deliver precise radiation treatments to patients, with space to add two more LINACs to meet future demand.
• MRI-guided precision radiation treatment – the first of its kind in Fort Worth – to facilitate therapy with unprecedented accuracy.
• Positron emission tomography (PET) imaging, which is critical for accurately diagnosing and evaluating tumor growth.
• A fully equipped brachytherapy suite to provide high-dose radiation treatments for patients with prostate or gynecologic cancers.

UT Southwestern’s cancer program is ranked among the top 25 out of 4,500 hospitals in the nation by U.S. News & World Report, and its Harold C. Simmons Comprehensive Cancer Center is the only National Cancer Institute-designated Comprehensive Cancer Center in North Texas and one of only 57 in the nation. UTSW also has the largest individual facility for radiation oncology in North Texas, with some of the most sophisticated treatment machines in the world. UTSW’s Department of Radiation Oncology specialists are pioneers in advanced therapies such as stereotactic ablative radiation therapy (SABR) and personalized ultrafractionated stereotactic adaptive radiotherapy (PULSAR), which have changed the standard of radiation therapy to make it more targeted and less damaging to healthy tissue.

Moncrief Cancer Institute has been a part of UT Southwestern since 1999, offering screening programs and educational and support services for multiple counties. In 2015, UT Southwestern expanded its cancer care to Fort Worth, offering medical and surgical oncology services, imaging, and chemotherapy.

The new Radiation Oncology campus will join UT Southwestern’s other specialty services provided at the nearby UT Southwestern Monty and Tex Moncrief Medical Center at Fort Worth. This outpatient facility offers primary care and lab services and an on-site retail pharmacy as well as specialty care clinics for cardiology, dermatology, endocrinology and endocrine surgery, neurology and neurosurgery, ophthalmology, otolaryngology (ear-nose-throat), rheumatology, and urology. Expanded imaging services, including 3T MRI, two ultrasound units, CT, and fluoroscopy, were added earlier this year.

Dr. Podolsky holds the Philip O’Bryan Montgomery, Jr., M.D. Distinguished Presidential Chair in Academic Administration and the Charles Cameron Sprague Distinguished Chair in Biomedical Science.

About UT Southwestern Medical Center 

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 140,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5.1 million outpatient visits a year.

DALLAS – May 08, 2025 – A protein identified by researchers at UT Southwestern Medical Center may drive resistance to immune checkpoint inhibitors, a widely used form of immunotherapy to treat cancer. The findings, published in Communications Medicine, link glycoprotein non-metastatic melanoma protein B (GPNMB) to relapse after treatment and suggest it may help tumors evade immune surveillance in metastatic renal cell carcinoma.

“Finding serum GPNMB as a predictor of acquired resistance and a potential target for overcoming that resistance to cancer immunotherapy could contribute to further improvement of the outcome of cancer patients,” said study leader Kiyoshi Ariizumi, Ph.D., Professor of Dermatology at UT Southwestern and a member of the Harold C. Simmons Comprehensive Cancer Center.

Kiyoshi Ariizumi, Ph.D., is Professor of Dermatology at UT Southwestern and a member of the Harold C. Simmons Comprehensive Cancer Center.

Checkpoint inhibitors improve survival for many patients with advanced cancers by removing the molecular “brakes” that prevent immune cells from recognizing and eliminating tumors. However, more than half of patients who initially respond to this type of immunotherapy eventually relapse due to acquired resistance within a few months to years of sustained treatment.

To better understand how this resistance develops, UT Southwestern researchers analyzed tumor and blood samples from 39 patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors. Among patients who initially responded positively, 28% developed resistance within two years, coinciding with rising levels of GPNMB in the blood. By comparing samples collected before treatment and after disease progression, the team investigated the molecular changes that may cause relapse.

Using RNA sequencing and whole exome analysis, the researchers found that GPNMB was significantly upregulated in tumors after relapse. Its increase in blood samples during disease progression raises the possibility of its use as a noninvasive biomarker to track treatment response. If validated, such a blood-based marker could help clinicians identify resistance earlier and adjust treatment accordingly.

The team traced the rise in GPNMB to a signaling cascade set in motion by immune checkpoint therapy itself. That same molecular pattern – which also appeared in the blood of relapsing patients – strengthened the connection between the laboratory findings and clinical outcomes.

In mouse models, blocking GPNMB restored CD8+ T cell activity – a critical component of the immune response – and improved the effectiveness of the therapy after it had stopped working. In another experiment, shutting off the gene that produces GPNMB also resensitized resistant tumors to treatment.

“Our findings have great promise in being able to establish personalized cancer medicine specialized for tumor recurrence and create novel inhibitors that restore tumor response to immunotherapy,” Dr. Ariizumi said.

He and other scientists at UTSW have investigated the role of GPNMB in suppressing immune responses to cancer for years. This new work builds on that foundation by directly linking GPNMB to therapy resistance in kidney cancer. Although the study focused on metastatic renal cell carcinoma, the researchers plan to collaborate with clinical oncologists at the Simmons Cancer Center to explore whether GPNMB-driven resistance also plays a role in other cancers treated with immune checkpoint inhibitors.

Other UTSW researchers who contributed to the study are first author Jin-Sung Chung, Ph.D., Instructor of Dermatology; Ponciano Cruz Jr., M.D., Professor of Dermatology; Hans Hammers, M.D., Ph.D., Professor of Internal Medicine in the Division of Hematology and Oncology and co-leader of the Experimental Therapeutics Research Program in the Simmons Cancer Center; Lin Xu, Ph.D., Assistant Professor in the Peter O’Donnell Jr. School of Public Health and of Pediatrics; and Lei Guo, Ph.D., Computational Biologist in the Quantitative Biomedical Research Center in the O’Donnell School of Public Health.

Dr. Xu is also a member of the Simmons Cancer Center.

The research was supported by the Department of Defense Kidney Cancer Research Program (W81XWH-20-1-0905), a VA Merit Award (1 I01 BX004069-01), and a National Cancer Institute (NCI) Cancer Center Support Grant (P30CA142543).

About UT Southwestern Medical Center   

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 140,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5.1 million outpatient visits a year.

DALLAS – April 30, 2025 – An FDA-designated orphan drug that can target a key vulnerability in lung cancer shows promise in improving the efficacy of radiation treatments in preclinical models, according to a study by UT Southwestern Medical Center researchers. The findings, published in Science Advances, suggest a new way to enhance the response to radiotherapy by inhibiting DNA repair in lung cancer cells.

“This study was motivated by challenges faced by millions of cancer patients undergoing radiation therapy, where treatment-related toxicities limit both curative potential and the patient’s quality of life,” said principal investigator Yuanyuan Zhang, M.D., Ph.D., Assistant Professor of Radiation Oncology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

Yuanyuan Zhang, M.D., Ph.D., is Assistant Professor of Radiation Oncology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

Prior research, including from the laboratory of co-investigator Ralph J. DeBerardinis, M.D., Ph.D., Professor and Director of the Eugene McDermott Center for Human Growth and Development, Professor in Children’s Medical Center Research Institute at UT Southwestern, and co-leader of the Cellular Networks in Cancer Research Program in the Simmons Cancer Center, has demonstrated that altered metabolic pathways in lung cancer cells allow them to survive, grow, and spread. But the role of metabolism in enhancing radiation efficacy has not been thoroughly explored. 

To identify metabolic pathways that allow cancer cells to survive radiation therapy, researchers conducted an unbiased CRISPR screen that identified lipoylation, a crucial process for mitochondrial enzyme function. Further investigation linked lipoylation deficiency to impaired DNA repair in cancer cells.

Lipoylation can be inhibited by the drug CPI-613, also known as devimistat, which received orphan drug status from the Food and Drug Administration (FDA). Orphan drugs are used to treat rare conditions and come with certain incentives to encourage their development given their small patient population. However, CPI-613 has not been found to improve outcomes on its own among patients with non-small cell lung cancer or in combination with surgical approaches in pancreatic cancer. In this study, researchers paired the drug with radiation to measure its effects in cancer cell lines and in mouse models of lung cancer.

Ralph J. DeBerardinis, M.D., Ph.D., is Professor and Director of the Eugene McDermott Center for Human Growth and Development and Professor in Children’s Medical Center Research Institute at UT Southwestern. He holds the Eugene McDermott Distinguished Chair for the Study of Human Growth and Development and the Philip O’Bryan Montgomery Jr., M.D., Distinguished Chair in Developmental Biology and is a Sowell Family Scholar in Medical Research.

“This study demonstrates for the first time that inhibiting lipoylation enhances lung cancer cells’ response to radiotherapy, offering a clinically translatable strategy using a clinically tested drug,” Dr. Zhang said.

Other UTSW contributors include first author Jui-Chung Chiang, Ph.D., postdoctoral researcher in the Zhang Lab; John D. Minna, M.D., Director and Professor of the Hamon Center for Therapeutic Oncology Research and co-leader of the Experimental Therapeutics Research Program in the Simmons Cancer Center; Robert D. Timmerman, M.D., Chair and Professor of Radiation Oncology; Anthony Davis, Ph.D., Associate Professor of Radiation Oncology; Zengfu Shang, Ph.D., Assistant Professor of Radiation Oncology; Ling Cai, Ph.D., Assistant Professor in the Peter O’Donnell Jr. School of Public Health; Feng Cai, Ph.D., Assistant Professor in Children’s Medical Center Research Institute at UT Southwestern; and Wei-Min Chen, Ph.D., postdoctoral researcher in Radiation Oncology.

Drs. DeBerardinis, Ling Cai, Davis, Minna, and Timmerman are members of the Simmons Cancer Center. Dr. DeBerardinis is a Howard Hughes Medical Institute Investigator and holds the Eugene McDermott Distinguished Chair for the Study of Human Growth and Development and the Philip O’Bryan Montgomery Jr., M.D., Distinguished Chair in Developmental Biology and is a Sowell Family Scholar in Medical Research.

This research was supported by the Howard Hughes Medical Institute Investigator Program, grants from the National Institutes of Health (R35CA220449, P50CA196516, P50CA070907, and P30CA142543), the Moody Foundation (Robert L. Moody, Sr. Faculty Scholar Award), Jerry and Emy Lou Baldridge, the ASCO Young Investigator Award, the Lung SPORE Career Enhancement Award, a Distinguished Research Award from the President’s Research Council, American Cancer Society Institutional Research Grant (IRG-21-142-16), National Cancer Institute Cancer Center Support Grant (P30CA142543), the National Center for Advancing Translational Sciences of the National Institutes of Health (KL2TR003981 and CTSA-PP-YR1-D-009), Startup Award from UT Southwestern Department of Radiation Oncology, the Once Upon a Time Foundation, and Cancer Prevention and Research Institute of Texas (CPRIT) grant (RP180770).

About UT Southwestern Medical Center   

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 140,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5.1 million outpatient visits a year.

DALLAS – April 29, 2025 – Black and Hispanic children with high-risk neuroblastoma experience worse survival outcomes than their white peers, even when treated in frontline clinical trials, according to a study led by a UT Southwestern Medical Center researcher. Published in JAMA Network Open, the study is believed to be the first to comprehensively evaluate survival by race and ethnicity in a national cohort of children with high-risk neuroblastoma enrolled in clinical trials. 

Neuroblastoma is a type of cancer that involves immature nerve cells and is the most common extracranial solid tumor in children.

Puja Umaretiya, M.D., M.S., is Assistant Professor of Pediatrics in the Division of Hematology and Oncology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

“The findings show that access to clinical trials alone is insufficient to overcome the inferior survival outcomes experienced by Black and Hispanic children with cancer,” said lead author Puja Umaretiya, M.D., M.S., Assistant Professor of Pediatrics in the Division of Hematology and Oncology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

Although racial and ethnic differences in childhood cancer survival have been previously documented, those datasets often lack important clinical treatment details to help understand why they occur. By using data from the Children’s Oncology Group, the research team was able to move beyond access and examine whether there are variations in survival even after accounting for access to highly specialized care as part of a clinical trial. The team also leveraged clinical trial data to examine potential mechanisms contributing to these differences in outcomes. 

The study analyzed data from two cohorts of children with high-risk neuroblastoma, including 696 children on chemotherapy induction/consolidation studies and 935 children on post-consolidation studies through the Children’s Oncology Group. The study found that Hispanic children had a nearly 80% higher hazard of death after treatment on induction trials compared to white patients after adjusting for tumor characteristics. In post-consolidation trials, both Black and Hispanic children had significantly lower survival rates than white children, even after researchers accounted for disease biology and response to early treatment.

The team found no significant racial or ethnic differences in care, including a lack of any delays during chemotherapy.

Dr. Umaretiya noted that her earlier research has shown children from racially and ethnically marginalized groups participate in frontline neuroblastoma trials at rates similar to white children. Despite this comparable access, racial and ethnic survival differences persist.

“These data identify the need for studies focused in two areas,” she said. “First, we need to be thoughtful about the data we collect on clinical trials to understand why marginalized groups do not experience the same outcomes. Collecting more specific data, such as social determinants of health, may provide insight into the underlying causes. Simultaneously, we need to embed supportive care interventions for groups at risk for worse outcomes despite standardized therapies.”

Previous work from Dr. Umaretiya’s team found that nearly three-quarters of Black and Hispanic families of children with cancer face at least one unmet health-related social need — such as food, housing, or transportation insecurity — which may affect outcomes.

“While further work is needed to understand disparate survival outcomes, any efforts to improve outcomes for children with cancer will likely need to focus on health-related social needs, which are highly prevalent and may contribute to worse outcomes in Black and Hispanic children,” Dr. Umaretiya said.

Sandi L. Pruitt, Ph.D., M.P.H., Professor in the Peter O’Donnell Jr. School of Public Health and Associate Director of Community Outreach and Engagement in the Simmons Cancer Center, also contributed to this study. Dr. Pruitt holds the Barrett Family Professorship in Cancer Research. 

The study was funded by the American Society of Clinical Oncology Young Investigator Award, a Children’s Oncology Group National Clinical Trials Network Statistics and Data Center grant (U10CA180899) and an Operations Center grant (U10CA180886), St. Baldrick’s Foundation, and the National Cancer Institute (NCI) Cancer Center Support Grant (P30CA142543).

About UT Southwestern Medical Center   

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 140,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5.1 million outpatient visits a year.

Satwik Rajaram, Ph.D., is Assistant Professor in the Lyda Hill Department of Bioinformatics and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

“There’s a real unmet need in the clinic to predict who will respond to certain therapies. Our work demonstrates that histopathological slides, a readily available resource, can be mined to produce state-of-the-art biomarkers that provide insight on which treatments might benefit which patients,” said Satwik Rajaram, Ph.D., Assistant Professor in the Lyda Hill Department of Bioinformatics and member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. Dr. Rajaram co-led the study with Payal Kapur, M.D., Professor of Pathology and Urology and a co-leader of the Kidney Cancer Program (KCP) at the Simmons Cancer Center.

Every year, nearly 435,000 people are diagnosed with clear cell renal cell carcinoma (ccRCC), making it the most common subtype of kidney cancer. When the disease metastasizes, anti-angiogenic therapies are often used for treatment. These drugs inhibit new blood vessels from forming in tumors, limiting access to molecules that fuel tumor growth. Although anti-angiogenic drugs are widely prescribed, fewer than 50% of patients benefit from them, Dr. Kapur explained, exposing many to unnecessary toxicity and financial burden.

Payal Kapur, M.D., is Professor of Pathology and Urology at UT Southwestern and a co-leader of the Kidney Cancer Program (KCP) at the Simmons Cancer Center.

No biomarkers are clinically available to accurately assess which patients are most likely to respond to anti-angiogenic drugs, she added, although a clinical trial conducted by Genentech suggested that the Angioscore (a test that assesses the expression of six blood vessel-associated genes) may have promise. However, this genetic test is expensive, is hard to standardize among clinics, and introduces delays in treatment. It also tests a limited part of the tumor, and ccRCC is quite heterogenous, with variable gene expression in different regions of the cancer.

To overcome these challenges, Drs. Kapur and Rajaram and their colleagues at the KCP developed a predictive method using AI to assess histopathological slides – thinly cut tumor tissue sections stained to highlight cellular features. These slides are nearly always part of a patient’s standard workup at diagnosis, and their images are increasingly available in electronic health records, said Dr. Rajaram, also Assistant Professor in the Center for Alzheimer’s and Neurodegenerative Diseases and the Department of Pathology.

Using a type of AI based on deep learning, the researchers “trained” an algorithm using two sets of data: one that matched ccRCC histopathological slides with their corresponding Angioscore, and another that matched slides with a test they developed that assesses blood vessels in the tumor sections.

A typical histopathologic slide image of kidney cancer tissue (left) has significant intra-slide heterogeneity, illustrated by the false coloring in the middle panel with two distinct regions. The dramatic change in blood vessels across these regions is marked as a green overlay.

Importantly, unlike many deep learning algorithms that don’t offer insight into their results, this approach is designed to be visually interpretable. Rather than producing a single number and directly predicting response, it generates a visualization of the predicted blood vessels that correlates tightly with the RNA-based Angioscore. Patients with more blood vessels are more likely to respond to therapy; this approach allows users to understand how the model reached its conclusions.

When the researchers evaluated this approach using slides from more than 200 patients who weren’t part of the training data – including those collected during the clinical trial that showed the potential value of Angioscore – it predicted which patients were most likely to respond to anti-angiogenic therapies nearly as well as Angioscore. The algorithm showed a responder will have a higher score than a non-responder 73% of the time compared to 75% with Angioscore. 

The study authors suggest AI analysis of histopathological slides could eventually be used to help guide diagnostic, prognostic, and therapeutic decisions for a variety of conditions. They plan to develop a similar algorithm to predict which patients with ccRCC will respond to immunotherapy, another class of treatments that only some patients respond to.

Other UTSW researchers who contributed to this study include first author Jay Jasti, Ph.D., former Data Scientist in the Rajaram Lab; James Brugarolas, M.D., Ph.D., Professor of Internal Medicine, Director of the Kidney Cancer Program, and a member of the Simmons Cancer Center; Dinesh Rakheja, M.D., Professor of Pathology and Pediatrics; Hua Zhong, Ph.D., Computational Biologist; Vandana Panwar, M.D., Medical Resident; Vipul Jarmale, M.S., Data Scientist; Jeffrey Miyata, B.S., Histology Technician; and Alana Christie, M.S., Biostatistical Consultant.

Dr. Kapur holds the Jan and Bob Pickens Distinguished Professorship in Medical Science, in Memory of Jerry Knight Rymer and Annette Brannon Rymer and Mr. and Mrs. W.L. Pickens.

The study was funded by the Department of Defense (KC200285), the Cancer Prevention and Research Institute of Texas (RP220294), the Lyda Hill Department of Bioinformatics, a National Institutes of Health-sponsored Kidney Cancer SPORE grant (P50CA196516), and a National Cancer Institute (NCI) Cancer Center Support Grant (P30CA142543).

About UT Southwestern Medical Center   

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 140,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5.1 million outpatient visits a year.

DALLAS – April 14, 2025 – The STING protein, known for helping cells fight viral infections by generating inflammation, also appears to function as a quality control sensor for organelles that serve as cellular waste disposal systems, UT Southwestern Medical Center researchers found. Their study, published in Molecular Cell, helps explain critical features of diseases called lysosomal storage disorders and could eventually lead to new treatments for these and other neurodegenerative diseases.

Nan Yan, Ph.D., (right) Professor and Vice Chair of Immunology and Professor of Microbiology, co-led the study with Immunology graduate student Zhen Tang, B.S. Dr. Yan is an Investigator in the Peter O’Donnell Jr. Brain Institute and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. He holds the Edwin L. Cox Distinguished Chair in Immunology and Genetics and is a Rita C. and William P. Clements, Jr. Scholar in Medical Research.

“STING is well known as an innate immune signaling protein. This study uncovered a new nonimmune function of STING,” said study leader Nan Yan, Ph.D., Professor and Vice Chair of Immunology and Professor of Microbiology at UT Southwestern.

There are more than 70 known lysosomal storage disorders (LSDs). These rare neurodegenerative diseases are characterized by the dysfunction of lysosomes, cellular organelles that break down various substances ready for disposal, including proteins, nucleic acids, and even other organelles, by digesting them in acid. This dysfunction allows substances that would normally be broken down to accumulate to harmful levels.

Inflammation in the nervous system is a prevailing symptom of these disorders. But why lysosomal dysfunction causes neuroinflammation has been unclear. In a 2021 study, Dr. Yan and colleagues showed that STING – short for stimulator of interferon genes – drives this symptom for one LSD, Niemann-Pick disease type C1 (NPC1).

To see whether STING is involved in other LSDs, Dr. Yan’s team at UTSW worked with a mouse model of an LSD called Krabbe disease with the same mutation found in human disease. In some of these animals, the researchers also deleted the gene for STING. Compared with animals that carried neither genetic defect, those with only the Krabbe mutation had a substantial increase in the activity of inflammatory genes, particularly in a type of nervous system cell called microglia. Consequently, they developed severe neuroinflammation by about a month of age. However, in those also missing the STING gene, this increased gene activity and neuroinflammation was substantially reduced.

Lu Sun, Ph.D., is Assistant Professor of Molecular Biology, an Investigator in the Peter O’Donnell Jr. Brain Institute, and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. He is a Southwestern Medical Foundation Scholar in Biomedical Research.

The researchers saw a similar phenomenon in mouse models for two other LSDs – palmitoyl-protein thioesterase 1 deficiency and lysosomal chloride channel deficiency. These and other LSD mouse models in the study were provided by Steven Gray, Ph.D., UTSW Professor of Pediatrics, in the Eugene McDermott Center for Human Growth and Development, of Molecular Biology, and of Neurology, who is an expert on gene therapy for LSD patients.

These results suggested STING drives neuroinflammation when lysosomes become damaged, a finding the researchers corroborated when they dosed healthy cells with a chemical that damages lysosomes. A closer look at gene expression in cells derived from the animal models showed that STING also increased the activity of genes associated with lysosome repair and new lysosome generation. Additional experiments in collaboration with Lu Sun, Ph.D., Assistant Professor of Molecular Biology and an expert on glial cells, showed this phenomenon depends on a protein called transcription factor EB (TFEB), which acts as a master controller of several lysosome-related genes.

Because the STING protein has multiple functional regions spanning the cell membrane, the researchers did additional experiments to determine which region might be responsible for lysosome generation. They found that the region located squarely within the cell membrane was key for this function. This “transmembrane” region is known to house a channel that helps membranous vesicles, such as lysosomes, regulate pH – a measure of acidity or alkalinity – by transporting pH-lowering protons across the membrane. Opening this channel on acidic vesicles releases protons, increasing the pH inside the vesicles and activating TFEB.

Dr. Yan and his colleagues hypothesize that because lysosomes normally degrade STING continuously, since it’s perpetually generated in cells, STING accumulation signals cells to kickstart the lysosome repair and generation pathway. In LSDs, this accumulation also prompts STING to generate inflammation. Thus, finding a way to dampen STING’s inflammatory role while encouraging its lysosome repair and generation role could offer a new way to treat LSDs, Dr. Yan said. Because lysosome dysfunction is also a prominent feature of other neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS), this strategy eventually could be used to treat these conditions as well.

Dr. Yan holds the Edwin L. Cox Distinguished Chair in Immunology and Genetics and is a Rita C. and William P. Clements, Jr. Scholar in Medical Research. Dr. Sun is a Southwestern Medical Foundation Scholar in Biomedical Research. Both are Investigators in the Peter O’Donnell Jr. Brain Institute and members of the Harold C. Simmons Comprehensive Cancer Center.

Other UTSW researchers who contributed to this study include first author Zhen Tang, B.S., Cong Xing, B.S., Antonina Araszkiewicz, M.S., and Devon Jeltema, B.S., all Immunology graduate students; Kun Yang, M.D., Ph.D., Instructor of Immunology; Wanwan Huai, Ph.D., postdoctoral fellow; Nicole Dobbs, Ph.D., Senior Scientist and Manager of the Yan Lab; and Yihe Zhang, B.S., Genetics, Development, and Disease graduate student.

This study was funded by grants from the National Institutes of Health (AI151708, AI185226, and NS122825) and UT Southwestern Endowed Scholar funds.

About UT Southwestern Medical Center   

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

DALLAS – April 09, 2025 – Using a novel method that gives a readout of which proteins are in specific locations within cells, UT Southwestern Medical Center researchers have identified a protein that plays a key role in cell adhesion and movement. Their findings, published in Cell Reports, could help researchers better understand diverse phenomena such as cancer metastasis and cell differentiation.

“Our lab has a longstanding interest in understanding how cells are spatially organized. This work developed a new biochemical method that uncovered the function of a poorly characterized protein called calmin,” said W. Mike Henne, Ph.D., Associate Professor of Cell Biology and Biophysics and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. He co-led the study with first author Holly Merta, Ph.D., a postdoctoral researcher in the Henne Lab.

Dr. Merta explained that she, Dr. Henne, and their colleagues were originally interested in better understanding how proteins are organized in the endoplasmic reticulum (ER), a cellular organelle with a broad range of functions including storing calcium, synthesizing some lipids and cholesterol, and transporting proteins to other cellular locations. Because the proteins performing these functions are thought to be organized into discrete locations within the ER, the researchers wanted to learn which proteins are found within these different locations.

W. Mike Henne, Ph.D., Associate Professor of Cell Biology and Biophysics, is a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

To do this, they developed an approach called sub-organelle spatial proteomics by combining the gene editing tool CRISPR with TurboID, an enzyme that adds a chemical tag onto all proteins that are in close proximity. These tagged proteins can then be isolated and identified. By strategically anchoring TurboID onto different proteins known to localize in specific regions of the cell interior, researchers can create a “map” of the protein landscape.

The researchers fused TurboID to four proteins known to be in different subregions of the ER, then worked with UTSW’s Proteomics Core to identify all the tagged proteins. When they examined which proteins were located in the ER’s membrane tubules, they were surprised to find calmin, a protein whose function was previously unknown.

A closer look showed calmin appeared to bind to F-actin, a protein that’s part of the cytoskeleton – a network of fibers that helps cells hold their shape, move, and connect with surfaces through sticky junctions called focal adhesions. When the researchers used a genetic trick to deplete calmin in motile cells, the cells moved significantly slower and developed more focal adhesions. Causing cells to overproduce calmin had the opposite effect.

Holly Merta, Ph.D., is a postdoctoral researcher in the Henne Lab at UT Southwestern.

Together, these findings suggested calmin is necessary to break down the F-actin fibers responsible for stabilizing focal adhesions, increasing adhesion turnover. Further experiments suggest calmin does this by increasing molecular signaling that relies on calcium stored in the ER.

Because calmin is often mutated in cancers, Drs. Henne and Merta said this protein may be pivotal for metastasis, the spread of cancer cells beyond the original tumor. Increasing focal adhesions could help metastatic cells survive in their new anatomical locations, establishing secondary tumors. Calmin has also been identified in developing neurons, where it may be important for growing the long extensions characteristic of these cells. The researchers plan to investigate these possibilities in future studies.

Other UTSW scientists who contributed to this study include Gaudenz Danuser, Ph.D., Chair and Professor of the Lyda Hill Department of Bioinformatics and Professor of Cell Biology; Arun Radhakrishnan, Ph.D., Professor of Molecular Genetics; Tadamoto Isogai, Ph.D., Assistant Professor in the Lyda Hill Department of Bioinformatics; Achinta Sannigrahi, Ph.D., postdoctoral researcher; and Kaitlynn Gov, B.S., graduate student researcher.

Dr. Henne holds the Martha Lee Foster Professorship in Brain Science and Medicine and is a W. W. Caruth, Jr. Scholar in Biomedical Research.

This study was funded by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (DK126887), the National Institute of General Medical Sciences (GM119768 and GM145399), the National Institutes of Health (HL160487, AI158357, T32 DK007307, F32 GM154450, and 1S10OD028630-01); The Welch Foundation (I-1873 and I-1793), the UT Southwestern Medical Center Endowed Scholars Program, the Leducq Foundation (19CVD04), and a National Cancer Institute (NCI) Cancer Center Support Grant (P30CA142543).

About UT Southwestern Medical Center   

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

DALLAS – April 08, 2025 – A preclinical model developed at UT Southwestern Medical Center that recapitulates a rare infant-onset form of diabetes suggests the condition stems from gradual damage to the pancreas through misregulation of a molecular pathway called the unfolded protein response (UPR). The findings, published in Molecular Metabolism, could one day lead to new ways to treat more common subsets of diabetes, including Types 1 and 2, which affect hundreds of millions worldwide.

Amanda Casey, Ph.D., is Assistant Professor of Molecular Biology at UT Southwestern.

“Our findings from this model, which carries the same genetic mutation as in human disease, provide insights into how beta cells may become dysfunctional during diabetes,” said Amanda Casey, Ph.D., Assistant Professor of Molecular Biology at UT Southwestern. Dr. Casey co-led the study with Kim Orth, Ph.D., Professor of Molecular Biology and Biochemistry and a Howard Hughes Medical Institute Investigator, and Jun Wu, Ph.D., Associate Professor of Molecular Biology. Drs. Orth and Wu are members of the Harold C. Simmons Comprehensive Cancer Center at UTSW.

Neonatal diabetes affects an estimated 1 in 90,000-to-160,000 live births worldwide. Researchers have identified several single-gene mutations that cause this condition. One such mutation occurs in the gene encoding FicD, an enzyme that regulates the activity of BiP, a protein that helps fold other proteins into the shapes they need to function.

Under normal conditions, FicD precisely controls BiP by switching it between active and inactive states, allowing cells to respond to changing demands. When FicD is mutated, it loses this regulatory activity, resulting in permanent inactivation of BiP. This persistent BiP inactivation leads to the buildup of unfolded proteins inside cells, chronically activating the UPR.

Kim Orth, Ph.D., is Professor of Molecular Biology and Biochemistry at UT Southwestern and a member of the Harold C. Simmons Comprehensive Cancer Center. She is a Howard Hughes Medical Institute Investigator, holds the Earl A. Forsythe Chair in Biomedical Science, and is a W.W. Caruth, Jr. Scholar in Biomedical Research.

To determine how mutated FicD causes neonatal diabetes, Drs. Casey and Orth worked with the Wu Lab to develop a mouse line that carries the same genetic mutation as humans with this disease. Surprisingly, the mice appeared normal at birth, Dr. Orth said. But by 5 weeks of age, the mice developed high blood sugar and low levels of circulating insulin – hallmarks of diabetes.

When the researchers searched for signs of UPR throughout tissues in the rodents’ bodies, they saw hyperactivation of this molecular pathway in both the liver and pancreas, with pancreatic function significantly more affected. A closer look at mice with the mutation showed that pancreatic cells gradually lost the organized structure typical of healthy tissue. Although the insulin-producing pancreatic beta cells didn’t die, they appeared to lose the gene expression necessary to produce insulin, leading to a gradual decrease in levels of this critical blood sugar-regulating hormone over time.

Jun Wu, Ph.D., is Associate Professor of Molecular Biology at UT Southwestern and a member of the Harold C. Simmons Comprehensive Cancer Center. He is a Virginia Murchison Linthicum Scholar in Medical Research.

Dr. Casey noted that a misregulated UPR has been found to play a role in both Type 1 and Type 2 diabetes. It’s unclear why the pancreas is unusually susceptible to damage from glitches in this molecular pathway. But if scientists can find a way to protect the pancreas from UPR-related damage, she said, they might be able to protect this organ from progressive damage in patients with diabetes, allowing its beta cells to continue producing insulin.

Other UTSW researchers who contributed to this study are Bret Evers, M.D., Ph.D., Assistant Professor of Pathology and Ophthalmology; Nathan Stewart, B.S., and Naqi Zaidi, B.S., Research Technicians; Hillery Gray, B.A., Orth Lab Manager; Hazel A. Fields, Registered Histotechnologist, Lab Technical Assistant; Masahiro Sakurai, Ph.D., Research Scientist; and Carlos Pinzon-Arteaga, D.V.M., Ph.D., Research Associate.

This study was funded by grants from The Welch Foundation (I-1561), Once Upon a Time Foundation, the National Institutes of Health (R35 GM134945, R21 1R21EY034597-01A1, GM138565-01A1, and HD103627-01A), UTSW Nutrition & Obesity Research Center (under National Institute of Diabetes and Digestive and Kidney Diseases/NIH award number P30DK127984), and New York Stem Cell Foundation.

Dr. Orth holds the Earl A. Forsythe Chair in Biomedical Science and is a W.W. Caruth, Jr. Scholar in Biomedical Research. Dr. Wu is a Virginia Murchison Linthicum Scholar in Medical Research.

About UT Southwestern Medical Center   

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

Female mosquito salivary glands could unlock key to malaria transmission

Malaria, responsible for hundreds of thousands of deaths each year worldwide, is caused by a parasite transmitted through the salivary glands of female Anopheles mosquitoes. Understanding the biology of these tissues is critical to developing new treatments for the disease, found mostly in tropical countries. Mosquitoes have an internal 24-hour clock that controls a variety of behaviors, including pheromone production, swarming, and mating. However, it has been unknown whether their salivary glands operate on a cyclic daily schedule.

To answer this question, researchers including Joseph Takahashi, Ph.D., Chair and Professor of Neuroscience at UT Southwestern Medical Center and an Investigator in the Peter O’Donnell Jr. Brain Institute, examined gene activity in Anopheles salivary glands. According to their findings, reported in Nature Microbiology, about half of the mosquitoes’ salivary gland genes had rhythmic expression, particularly those important for efficient feeding, such as genes that make anticlotting proteins. The researchers also found that the mosquitoes preferred to feed at night, with the blood volume they ingested varying cyclically throughout the day.

Additionally, genes of the parasites living in Anopheles salivary glands had cyclic differences in activity, especially those involved in parasite transmission. The authors suggest the internal clocks of the parasite, mosquito, and mammalian host play an important role in successful malaria infection.

Study senior author Filipa Rijo-Ferreira, Assistant Professor of Infectious Diseases and Vaccinology at the University of California, Berkeley, is a former postdoctoral researcher in the Takahashi Lab at UTSW.

Nanoparticles extend glioblastoma survival in phase one trial

Despite decades of research to develop effective treatments, the median survival for glioblastoma – the most common malignant primary brain tumor in adults – is just 15-18 months after diagnosis. One reason for this grim statistic is that these tumors invariably recur despite aggressive, multimodality treatments. Although traditional radiation treatments can delay recurrence and extend survival, they often damage healthy brain tissue, negatively affecting quality of life. Preclinical research has suggested radiation-emitting nanoparticles targeting tumor-containing regions through convection enhanced delivery (CED), bypassing the blood-brain barrier, could effectively treat these tumors.

In a phase one clinical trial reported in Nature Communications, two researchers from UT Southwestern and their colleagues showed this strategy was safe and effective. The team worked with 21 patients at medical centers, including UTSW, who had recurrent glioblastoma. They were divided into six groups, each of which received a different dose of radiation-emitting nanoparticles through CED. Patients who received the highest doses had tolerable side effects and lived an average of 17 more months after treatment, significantly longer than expected for patients with recurrent glioblastoma. The authors suggest this strategy shows promise for improving treatments for these patients.

UTSW researchers who contributed to this study are Toral Patel, M.D., Associate Professor of Neurological Surgery, and Michael Youssef, M.D., Assistant Professor of Neurology. Drs. Patel and Youssef are members of the O’Donnell Brain Institute and the Harold C. Simmons Comprehensive Cancer Center at UTSW.

Alternate antidepressant not effective for Alzheimer’s agitation

Up to 60% of people with Alzheimer’s disease experience agitation, a symptom that can be a significant burden for caregivers. Nondrug treatments are recommended as first-line interventions. Citalopram, a selective serotonin reuptake inhibitor (SSRI) commonly prescribed for anxiety and depression, has shown promise for treating Alzheimer’s-induced agitation in patients whose symptoms don’t respond to other therapies. However, this drug has been linked to cardiac and cognitive risks. More specifically, citalopram consists of two compounds that are mirror images, R- and S-citalopram, and it is thought that the R-compound is linked to these risks.

Hoping to reap the same benefits without these risks, researchers in the U.S. and Canada evaluated the S-compound on its own, an available SSRI called escitalopram, in a phase three clinical trial. Results reported in Nature Medicine by Tarek Rajji, M.D., Chair and Professor of Psychiatry and in the O’Donnell Brain Institute at UT Southwestern, and colleagues showed that escitalopram was not effective in treating Alzheimer’s agitation. The drug also was associated with significant side effects including falls, diarrhea, and heart problems.

The authors suggest that citalopram should remain the preferred SSRI for treating Alzheimer’s-related agitation.

About UT Southwestern Medical Center 

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

DALLAS – March 21, 2025 – Members of UT Southwestern Medical School’s Class of 2025 gathered with anticipation inside the Bryan Williams, M.D., Student Center gymnasium Friday morning to learn where they will begin the next phase of their training as residents. The Dallas Mavericks’ drumline led the crowd in a countdown, and at precisely 11 a.m. the students opened their Match Day envelopes, joining thousands of other aspiring physicians nationwide in this annual rite of passage.

Cheers abounded as 222 UT Southwestern students, surrounded by friends and family, proudly showed off their matches with more than 80 residency programs across the U.S. After graduating in May, they will be heading to prestigious hospitals across the country, including Massachusetts General, Johns Hopkins, UCSF, and Northwestern. Seventy-five students will continue their training at UTSW-affiliated programs, which rank among the best in the nation.

U.S. News & World Report named UT Southwestern among its Best Medical Schools for 2024-25. UTSW has the largest graduate medical education training program in Texas, with more than 1,400 clinical residents completing their medical education with postgraduate specialty and subspecialty training.

“Match Day is a momentous occasion that celebrates our students and all they have accomplished over the past four years,” said Angela Mihalic, M.D., Dean of Medical Students and Associate Dean for Student Affairs at UT Southwestern Medical School, Professor of Pediatrics, and a Distinguished Teaching Professor.

“This milestone marks the beginning of a new chapter. As the members of the Class of 2025 prepare to embark on the next phase of their medical training, we feel confident that their exceptional achievements at UT Southwestern will only lead to greater success and improve the lives of countless patients with competence and compassion,” she said. “We are exceedingly proud to have helped train the next generation of primary care and specialty physicians who will answer a critical call of this nation.”

This year, the National Resident Matching Program matched more than 40,000 medical students to institutions across the country. Top specialty selections for UT Southwestern students include Internal Medicine, Family Medicine, Pediatrics, and Anesthesiology.

“It sounds cliché, but I can’t remember ever wanting to pursue a career besides medicine,” said Ruchita Iyer, who will train in Internal Medicine-Pediatrics at UT Southwestern. “Reflecting on my education, I am beyond grateful to have completed my medical training at UTSW, where I have developed the foundation to become a well-rounded, empathic physician.”

“After my family moved to Texas in 2020, I wanted to stay close to home while pursuing a world-class medical education,” Pooja Venkatesh, soon to train in Neurosurgery at Emory University, said of her decision to complete medical school at UT Southwestern. “I knew UTSW would be a place where I could thrive, both professionally and personally.”

UTSW training opportunities, rankings, distinctions

UT Southwestern’s training facilities include William P. Clements Jr. University Hospital, ranked by U.S. News & World Report as the No. 1 hospital in Dallas-Fort Worth for eight consecutive years; Parkland Memorial Hospital, one of the nation’s busiest public hospitals; and Children’s Medical Center Dallas, one of the largest children’s hospitals in the country and the only hospital in North Texas to be ranked in all pediatric specialties in U.S. News’ annual Best Children’s Hospitals report. UT Southwestern also houses a 49,000-square-foot Simulation Center – one of the largest of its kind.

UT Southwestern is nationally ranked among the best hospitals by U.S. News in 11 specialties, the most of any in Texas: cancer; cardiology, heart, and vascular surgery; diabetes and endocrinology; ear, nose, and throat; gastroenterology and gastrointestinal surgery; geriatrics; neurology and neurosurgery; orthopaedics; pulmonology and lung surgery; rehabilitation; and urology. It is also rated “High Performing” in 19 out of 20 adult procedures and conditions, from aortic valve surgery and hip replacement to back surgery (spinal fusion) and stroke care.

Other key distinctions

• UT Southwestern Medical School is ranked Tier 1 in research according to U.S. News & World Report’s 2024-25 Best Medical Schools rankings.
• UTSW’s Harold C. Simmons Comprehensive Cancer Center is the only National Cancer Institute-designated comprehensive cancer center in North Texas – one of only 57 across the U.S.
• UTSW is designated as an Advanced Comprehensive Stroke Center by The Joint Commission and the American Heart Association/American Stroke Association and has a Level 4 Epilepsy Center, the highest possible rating awarded by the National Association of Epilepsy Centers.
• UTSW scientists currently lead more than 5,990 research projects annually, supported by more than $767 million in funding.
• The Perot Family Scholars Medical Scientist Training Program, one of just 54 M.D./Ph.D. training programs in the country supported by the National Institutes of Health (NIH), offers a dual degree to strengthen the advancement of laboratory discoveries into the clinical arena.
• UTSW ranked No. 3 in the 2024 Nature Index among global health care institutions for its published research.
• UTSW is ranked second overall in Comprehensive Academic Medical Centers (AMCs) for Patient Experience reported by Vizient, which includes 97% of all AMCs.
• UTSW was awarded Press Ganey’s 2024 Guardian of Excellence Award, which recognizes the top 5% of health care providers in delivering patient experience. It also received the Pinnacle of Excellence Award, which commends patient experience scores over a three-year time frame.

About UT Southwestern Medical Center   

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

DALLAS – March 11, 2025 – A new “self-driving” microscope developed by UT Southwestern Medical Center researchers solves two fundamental challenges that have long plagued microscopy: first, imaging living cells or organisms at dramatically different scales, and second, following a specific structure or area of interest over long periods of time. This innovation, detailed in Nature Methods, is already making observations that have not been possible with conventional methods.

Reto Fiolka, Ph.D., (left) is Associate Professor in the Lyda Hill Department of Bioinformatics and of Cell Biology at UT Southwestern. Stephan Daetwyler, Ph.D., is Instructor in the Hill Department of Bioinformatics.

“Our work demonstrates a significant advancement in integrated bioimaging, enabling long-term observation of biological dynamics across scales from cellular to systemic levels to ultimately better understand developmental and disease processes,” said Reto Fiolka, Ph.D., Associate Professor in the Lyda Hill Department of Bioinformatics and of Cell Biology at UT Southwestern. Dr. Fiolka co-led development of the new microscope with Stephan Daetwyler, Ph.D., Instructor in the Lyda Hill Department of Bioinformatics.

For two decades, Dr. Daetwyler explained, researchers have made a wealth of biological discoveries using a technique called light-sheet microscopy, in which a thin plane of light excites fluorescent probes added to a sample to tag specific structures. Because the light causes these probes to glow, researchers could easily find and image the tagged structures, allowing for a deeper comprehension of their role in health and disease.

However, Dr. Daetwyler said, light-sheet microscopy comes with a significant drawback: The higher the imaging resolution, the smaller the area researchers can image. Thus, scientists have had to choose which resolution and field of view they required before starting an experiment. Therefore, they could either image living whole organisms at low resolution, or a few cells and their internal structures at high resolution. This limitation has significantly hindered understanding of biological processes, since most of them happen on the cellular, tissue, and organismal levels, Dr. Daetwyler said.

To address this challenge, Drs. Fiolka and Daetwyler and their colleagues combined hardware that performs low-resolution light-sheet microscopy, known as multidirectional selective plane illumination microscopy (mSPIM), with hardware that performs a type of high-resolution light-sheet microscopy called axially swept light-sheet microscopy (ASLM, developed at UTSW in 2015). To switch between the two modalities within a second, the team created a novel custom microscope hardware control software.

In this part of the microscope, the high-resolution light-sheet is pivoted back and forth for making the axially swept light-sheet modality for high-resolution imaging, and the low- and high-resolution light-sheets are combined onto the same illumination path.

Another challenge with light-sheet microscopy has been tracking structures over time, Dr. Fiolka added. Most biological processes are dynamic, he explained. Organisms grow, and cells move and multiply, requiring human intervention to frequently redirect the microscope’s field of view – a tedious task when imaging biological processes that take place over hours or days.

To find a solution, the researchers incorporated a tracking mode in the new microscope’s control software to imbue it with a “self-driving” function, allowing the microscope’s field of view to follow a specific region of interest – which users register during an initialization step – for hours or even days.

As proof of principle, the researchers imaged human cancer cells injected into zebrafish larvae, transparent organisms a few millimeters long that are frequently used as biological models for cancer research. The researchers saw that osteosarcoma cells – a type of bone cancer – were readily attacked and cleared by immune cells called macrophages. However, skin cancer cells were not cleared from the organism, despite close interactions with the immune cells. Zooming in on the macrophages, the team observed changes in shape that correlated with their current biological function – for example, circulating macrophages had a different shape compared with those at different stages of immune attack.

Several colleagues at UTSW are already using the new platform in their research, Drs. Daetwyler and Fiolka said. The control software for the new microscope is open source, allowing researchers elsewhere to customize it for their needs.

“A broader understanding of biological processes across scales will impact our knowledge about many diseases,” Dr. Daetwyler said. “This includes cancer progression, metastasis, developmental disorders, systemic diseases, and cardiovascular diseases, to name just a few.”

Other UTSW researchers who contributed to this study include Gaudenz Danuser, Ph.D., Chair and Professor of the Lyda Hill Department of Bioinformatics; Rolf Brekken, Ph.D., Professor of Surgery, in the Hamon Center for Therapeutic Oncology Research, and of Pharmacology; Felix Zhou, Ph.D., and Dagan Segal, Ph.D., Instructors in the Lyda Hill Department of Bioinformatics; Jill Westcott, Ph.D., research scientist; and Hanieh Mazloom-Farsibaf, Ph.D., and Bingying Chen, Ph.D., postdoctoral researchers.

The “self-driving” microscope developed by UT Southwestern scientists enables imaging and analysis across scales – from imaging an entire organism (top) to imaging immune-cancer cells' interaction with sub-cellular resolution (below and right).

Dr. Fiolka is a member of the Harold C. Simmons Comprehensive Cancer Center.

This study was funded by grants from the Swiss National Science Foundation (191347), the National Institute of General Medical Sciences (R35 GM133522), and the National Cancer Institute (U54 CA268072 and K99CA270285).

About UT Southwestern Medical Center   

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

DALLAS – March 10, 2025 – While randomized comparative trials are needed, a relatively new treatment option for upper urinary tract cancers shows promise for lowering long-term recurrence in many patients with low-grade disease, according to a multicenter study led by researchers at UT Southwestern Medical Center.

Solomon Woldu, M.D., is Associate Professor of Urology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

UGN-101 – a reverse thermal mitomycin gel sold under the brand name Jelmyto – was the first FDA-approved treatment for upper tract urothelial carcinoma (UTUC). Since the drug entered the market in 2020, researchers at 15 academic and community centers have collaborated to measure its effectiveness and better understand possible adverse effects. This latest study, published in Urologic Oncology, found that UGN-101 resulted in three-year, recurrence-free survival in 65% of patients with low-grade UTUC who had an initial complete response.

“This is a relatively rare type of cancer and one that is difficult to treat,” said the study’s corresponding author, Solomon Woldu, M.D., Associate Professor of Urology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. “The durability of response we observed is promising because it suggests that UGN-101 may provide long-term benefit as a maintenance therapy, extending patients’ lives beyond what was possible before without the need for kidney or ureter removal and lifelong dialysis.”

The retrospective data review included 132 patients treated with UGN-101 at the 15 institutions. Of those, 55 had no evidence of disease on the first endoscopic evaluation following UGN-101 induction. Those patients were included in the recurrence analysis to determine the longer-term efficacy of the treatment at three years.

The study builds on earlier research by the multi-institutional cohort, published in 2023, showing UGN-101’s effectiveness at three months after treatment.

Yair Lotan, M.D., is Chief of Urologic Oncology, Professor of Urology, and a member of the Experimental Therapeutics Research Program at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

UGN-101 is administered via a catheter directed into the lining of the kidney. Once the catheter is in place, the body’s natural temperature activates the gel, releasing mitomycin to target any remaining cancer cells. Because the mitomycin is gel-based, it remains in contact with the upper urinary tract longer, increasing its effectiveness. After diagnosis of a low-grade UTUC, treatment plans include an induction course of six weekly doses administered either through a nephrostomy in the kidney in the outpatient clinic or via a ureteral catheter in the operating room. In some patients, additional maintenance doses are administered monthly. 

“While UGN-101 may offer benefits to a cohort of patients with low-grade cancers, we still have work to do to better understand even longer-term outcomes, the risks and benefits of maintenance therapy, and the clinical guidelines for effectively administering therapy over many years,” said study leader Yair Lotan, M.D., Chief of Urologic Oncology, Professor of Urology, and a member of the Experimental Therapeutics Research Program at Simmons Cancer Center.

Brett Johnson, M.D., and Isamu Tachibana, M.D., Assistant Professors of Urology at UT Southwestern, also contributed to this study. 

Drs. Woldu and Lotan serve as consultants for UroGen Pharma Ltd., which manufactures UGN-101.

Dr. Lotan holds the Jane and John Justin Distinguished Chair in Urology, in Honor of Claus G. Roehrborn, M.D.

About UT Southwestern Medical Center   

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

DALLAS – March 04, 2025 – Using a powerful microscopy technique, a team led by researchers at UT Southwestern Medical Center has gained insights into how the body uses vitamin K, an essential nutrient that plays a pivotal role in blood clotting and other physiological functions. Their findings, published in Nature, could eventually help scientists develop new anticoagulants to prevent or treat conditions including strokes, heart attacks, atrial fibrillation, and deep vein thrombosis, a type of clot that usually occurs in the legs.

Xiaofeng Qi, Ph.D., is Assistant Professor of Molecular Biology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. He is a Cancer Prevention and Research Institute of Texas Scholar (CPRIT) and a Michael L. Rosenberg Scholar in Medical Research.

“This research paves the way for innovative anticoagulation therapies by targeting the enzyme GGCX, a novel approach with the potential to overcome the limitations of current vitamin K antagonists such as warfarin,” said Xiaofeng Qi, Ph.D., Assistant Professor of Molecular Biology and member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. “This could result in safer, more effective options for patients with coagulation disorders.”

Vitamin K, which is fat-soluble and found in sources including leafy green vegetables, carrots, and organ meat, is necessary to activate a variety of proteins. These proteins are not only pivotal for clotting but also for bone and heart health, energy metabolism, brain development, and fertility, among other roles. Vitamin K activates these proteins through a chemical reaction called carboxylation, which is mediated by an enzyme called gamma-glutamyl carboxylase (GGCX). But how GGCX facilitates this reaction has been unclear.

To answer this question, Dr. Qi and his colleagues used cryo-electron microscopy (cryo-EM). By freezing molecules at temperatures around minus 196 C (about minus 320 F) and bombarding them with streams of electrons, cryo-EM produces images that can show the molecules’ three-dimensional structures at atomic resolution.

Dr. Qi’s team worked with UTSW’s Cryo-Electron Microscopy Facility to perform cryo-EM on GGCX alone, when it was bound to a vitamin K-dependent protein called osteocalcin that plays a critical role in bone metabolism, and when it was bound to both osteocalcin and vitamin K. The findings showed that GGCX had a disordered structure when it wasn't bound to other molecules. But when bound to osteocalcin, GGCX formed a pocket of the right shape and size to attach to vitamin K. The structure of GGCX bound to both osteocalcin and vitamin K confirmed that vitamin K attached to the pocket, bringing osteocalcin and vitamin K in close contact to perform carboxylation.

Surprisingly, the researchers saw another molecule in all three structures. A closer look showed that it was cholesterol, which seems to play a role in stabilizing GGCX’s structure to facilitate binding to both osteocalcin and vitamin K. This role of cholesterol in vitamin K-dependent molecular pathways was previously unknown, Dr. Qi said. Now that scientists know the structure of GGCX and how it interacts with both vitamin K and its dependent proteins, Dr. Qi added, they could design drugs that interfere with binding.

“Structure is a powerful way to reveal a molecule’s function,” Dr. Qi said. “Here, we see the structure of vitamin K and its dependent protein binding to a critical enzyme, shedding light on how the chemical reaction that activates vitamin K-dependent proteins takes place.”

Dr. Qi said this study builds on his earlier postdoctoral work in the UTSW lab of Xiaochun Li, Ph.D., Associate Professor of Molecular Genetics and Biophysics. They collaborated to investigate cholesterol synthesis regulation with Nobel Laureates Michael S. Brown, M.D., Professor of Molecular Genetics and Internal Medicine, and Joseph L. Goldstein, M.D., Chair and Professor of Molecular Genetics, as well as Russell DeBose-Boyd, Ph.D., Professor of Molecular Genetics.

Other UTSW researchers who contributed to this study include first author Rong Wang, Ph.D., Senior Research Scientist; Baozhi Chen, M.D., Manager of the Qi Lab; Alyssa Ayala, B.S., Research Assistant; and Ning Zhou, Ph.D., Postdoctoral Researcher.

Drs. Brown and Goldstein are Regental Professors at UTSW. Dr. Brown is Director of the Erik Jonsson Center for Research in Molecular Genetics and Human Disease. Dr. Brown holds the W.A. (Monty) Moncrief Distinguished Chair in Cholesterol and Arteriosclerosis Research and the Paul J. Thomas Chair in Medicine. Dr. Goldstein holds the Julie and Louis A. Beecherl, Jr. Distinguished Chair in Biomedical Research and the Paul J. Thomas Chair in Medicine. Dr. DeBose-Boyd holds the Beatrice and Miguel Elias Distinguished Chair in Biomedical Science. Dr. Li is a Rita C. and William P. Clements, Jr. Scholar in Biomedical Research. Dr. Qi is a Cancer Prevention and Research Institute of Texas Scholar (CPRIT) and a Michael L. Rosenberg Scholar in Medical Research. 

This study was funded by grants from the National Institutes of Health (P01HL160487), the Endowed Scholars Program in Medical Science of UT Southwestern Medical Center, and CPRIT (RR230054).

About UT Southwestern Medical Center

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

Bhavya R. Shah, M.D., is Associate Professor of Radiology and Neurological Surgery at UT Southwestern as well as in the Advanced Imaging Research Center. He is also an Investigator in the Peter O'Donnell Jr. Brain Institute and a member of the Center for Alzheimer's and Neurodegenerative Diseases.

“This is the first study to use HIFU as a controlled model to evaluate brain injury biomarker dynamics,” said Bhavya R. Shah, M.D., Associate Professor of Radiology and Neurological Surgery at UT Southwestern as well as in the Advanced Imaging Research Center. He’s also an Investigator in the Peter O’Donnell Jr. Brain Institute and a member of the Center for Alzheimer’s and Neurodegenerative Diseases. “The ability to pair a timed pre- and post-HIFU measurement with precise lesion delivery is unprecedented and offers extraordinary potential for validating blood biomarkers of brain injury in a way that has not been done before.”

Dr. Shah co-led the study with Nil Saez-Calveras, M.D., a fourth-year Neurology resident at UT Southwestern.

Every year, nearly 800,000 people in the U.S. have a stroke, according to the Centers for Disease Control and Prevention. This condition is characterized by inadequate blood flow to regions of the brain, causing brain cells to die from a lack of oxygen. Although strokes can be diagnosed using magnetic resonance imaging (MRI), delays in care can lead to worse outcomes, explained Dr. Shah, who is also a member of the Harold C. Simmons Comprehensive Cancer Center at UTSW.

Nil Saez-Calveras, M.D., is a fourth-year Neurology resident at UT Southwestern.

In 2016, the Food and Drug Administration approved a new treatment for tremor disorders in which physicians use HIFU to burn away a targeted portion of the thalamus, the brain region where many types of tremors originate. Six years later, Dr. Shah and his colleagues reported a new technique that significantly improved HIFU targeting for this treatment. Recently, the team realized that the controlled brain injury caused by this therapy looks indistinguishable from stroke in brain imaging – the two types of damage have several features in common, including how the brain responds to these injuries, Dr. Shah said.

The researchers wondered whether this similarity could help them achieve a long-held goal of diagnosing stroke and brain injury through markers in the blood, Dr. Saez-Calveras said. Research toward this end has been stymied by a lack of blood measurements taken before stroke occurs, differences in where brain injury occurs in stroke patients, uncertainty about when a stroke occurred, and physiological differences among patients.

They reasoned that using the HIFU treatment as a research tool could overcome these challenges. In the new study, 30 patients at UTSW with tremor-dominant Parkinson’s disease or another movement disorder called essential tremor received HIFU to treat these conditions. The researchers collected blood samples immediately before the procedure, as well as one hour and 48 hours after. They then measured the concentrations of five molecular markers that previous research suggested might hold promise for diagnosing brain injuries: GFAP, neurofilament light chain, amyloid-beta 40, amyloid-beta 42, and phosphorylated tau 181 (pTau-181).

A coronal magnetic resonance imaging section shows a high-intensity focused ultrasound lesion in the left thalamus of the brain.

Forty-eight hours after HIFU treatment, all the molecular markers except pTau-181 had risen significantly; however, GFAP rose the most, more than quadrupling on average compared to pre-treatment measurements.

Based on these findings, Dr. Saez-Calveras said, GFAP could hold significant promise as a marker for stroke and other types of brain injury. The researchers plan to continue to study GFAP’s rise at different points after HIFU treatment to determine its feasibility as a diagnostic marker for brain injury. In addition, they are investigating hundreds of other molecules as potential candidates that might suggest possible brain injury earlier than GFAP. The team has also begun collecting blood from emergency stroke patients to determine if GFAP is elevated.

“Our study validates the use of focused ultrasound as a platform for biomarker discovery for brain diseases,” Dr. Saez-Calveras said.

Other UTSW researchers who contributed to this study include Marc Diamond, M.D., Director of the Center for Alzheimer’s and Neurodegenerative Diseases and Professor of Neurology and Neuroscience; Padraig O’Suilleabhain, M.D., Professor of Neurology; Barbara Stopschinski, M.D., Assistant Professor of Neurology and in the Center for Alzheimer's and Neurodegenerative Diseases; Jaime Vaquer-Alicea, Ph.D., Assistant Professor in the Center for Alzheimer's and Neurodegenerative Diseases and of Biochemistry; and Alexander Asturias, D.O., and James Yu, M.D., Radiology residents.

Drs. Diamond, Stopschinski, and Vaquer-Alicea are Investigators in the O’Donnell Brain Institute.

The study was funded by grants from the Presbyterian Foundation and the Patrick and Beatrice Haggerty Foundation.

About UT Southwestern Medical Center   

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

DALLAS – Feb. 25, 2025 – Multidrug resistance in cancer can be overcome by combining a drug that blocks a key enzyme with another anticancer drug, according to a study in preclinical models led by researchers at UT Southwestern Medical Center. The findings, published in Science Advances, could have implications for patients with certain cancers that have KRAS-G12C mutations after resistance to drug therapy develops.

Xinxin Song, M.D., Ph.D., is Assistant Professor of Surgery at UT Southwestern and member of the Harold C. Simmons Comprehensive Cancer Center.

“By overcoming resistance mechanisms, this combination therapy approach could improve treatment outcomes for patients with KRAS-G12C mutant cancers,” said the study’s lead author, Xinxin Song, M.D., Ph.D., Assistant Professor of Surgery at UT Southwestern and member of the Harold C. Simmons Comprehensive Cancer Center.

Cancers such as non-small cell lung cancer (NSCLC), colorectal cancer, and pancreatic ductal adenocarcinoma are driven by a mutant form of the KRAS protein that had long been considered undruggable. Such cancers have recently been treated with a KRAS-G12C inhibitor known as adagrasib, or MRTX849. However, emerging drug resistance to this therapy has presented challenges.

Daolin Tang, M.D., Ph.D., is Professor of Surgery at UT Southwestern and member of the Harold C. Simmons Comprehensive Cancer Center.

In order to investigate potential targets, Dr. Song, study leaders Daolin Tang, M.D., Ph.D., Professor of Surgery, and Rui Kang, M.D., Ph.D., Associate Professor of Surgery, and their colleagues first established the mechanism by which the mutant proteins were able to circumvent drug therapy. Using a variety of techniques, the researchers identified key steps in the complex cascade of cellular events that led to adagrasib becoming less effective. They found that one kinase, SRC, was key in this process.

Next, the researchers looked at more than 1,400 drug candidates and tested their ability to overcome the resistance that developed with adagrasib. They found that combining adagrasib with an SRC inhibitor called dasatinib improved the therapeutic efficacy against KRAS-G12C-mutated cells.

To test the potential clinical relevance of their findings, the researchers tested adagrasib both alone and together with dasatinib to determine their antitumor effects in both preclinical mouse models and human organoids. Bosutinib and DGY-06-116, a highly selective covalent SRC inhibitor, were also tested. Researchers found that by therapeutically targeting SRC, they could enhance or restore the anticancer activity of adagrasib.

Rui Kang, M.D., Ph.D., is Associate Professor of Surgery at UT Southwestern and member of the Harold C. Simmons Comprehensive Cancer Center.

“This research highlights the potential of targeting SRC kinase to prevent or overcome multidrug resistance after treatment with KRAS-G12C inhibitors,” Dr. Song explained. “Our findings could offer a transformative approach to improving therapeutic outcomes in certain KRAS-G12C mutant tumors.”

Other UTSW researchers who contributed to this research are John D. Minna, M.D., Director and Professor of the Hamon Center for Therapeutic Oncology Research, Professor of Internal Medicine and Pharmacology, and co-leader of the Experimental Therapeutics Research Program in the Simmons Cancer Center; Herbert J. Zeh, M.D., Chair and Professor of Surgery; Zhuan Zhou, Ph.D., Assistant Professor of Surgery; Boning Gao, Ph.D., Assistant Professor in the Hamon Center for Therapeutic Oncology Research and of Pharmacology; Chunhua Yu, M.D., Ph.D., Manager of the Tang Lab; and Ammar Elmezayen, Ph.D., postdoctoral researcher.

The SRC inhibitor DGY-06-116 was developed by Kenneth Westover, M.D., Ph.D. Chief of Lung Radiation Oncology Service, Director of Clinical Innovation and Information Systems for the Department of Radiation Oncology, and Associate Professor of Radiation Oncology and Biochemistry at UT Southwestern. Dr. Westover, who contributed to this study, is an inventor on a patent involving DGY-06-116.

Drs. Tang, Kang, Minna, Zeh, Zhou, Westover, and Gao are members of the Simmons Cancer Center.

This work was supported by grants from the National Institutes of Health (R01CA160417; R01CA229275; R01CA211070; CA070907; CA224065; CA142543; R01CA244341); The Welch Foundation (I-1829); Cancer Prevention and Research Institute of Texas (RP220145); American Cancer Society (IRG-21-142-16); Elsa U. Pardee Foundation (21005817); Anna Fuller Fund (21005962); and National Cancer Institute Cancer Center Support Grant (P30CA142543).

About UT Southwestern Medical Center   

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

Ralph J. DeBerardinis, M.D., Ph.D., Professor and Director of the Eugene McDermott Center for Human Growth and Development and Professor in Children’s Medical Center Research Institute at UT Southwestern, has been a Howard Hughes Medical Institute Investigator since 2018.

DALLAS – Feb. 19, 2025 – In localized non-small cell lung cancer (NSCLC), a tumor’s ability to use carbon from glucose to feed the tricarboxylic acid (TCA) cycle predicts cancer spread beyond the lung, months to years before metastases are clinically apparent. According to this new research from Children’s Medical Center Research Institute at UT Southwestern (CRI) published in Cancer Discovery, tumors with this metabolic activity result in early patient death. 

Ralph J. DeBerardinis, M.D., Ph.D., Professor and Director of the Eugene McDermott Center for Human Growth and Development at UT Southwestern and Professor in CRI, along with his former postdoctoral fellows — co-senior author Brandon Faubert, Assistant Professor of Medicine at the University of Chicago, and first author Ling Cai, Ph.D., Assistant Professor in the Peter O’Donnell Jr. School of Public Health at UT Southwestern — developed an isotope infusion assay to study cancer metabolism in 90 patients while their tumors were being surgically removed.

The scientists followed patients for up to 11 years after surgery to assess cancer progression and survival as part of a long-standing collaboration with Kemp Kernstine, M.D, Ph.D., Professor of Cardiovascular & Thoracic Surgery at UT Southwestern.

“Through this prospective, longitudinal study to assess metabolic properties in human non-small cell lung cancers, we specifically sought out properties that correlate with how the cancer progressed after the primary tumor was removed,” Dr. DeBerardinis said. “We wanted to see which cancers metastasized faster because blocking the pathways used by those tumors to spread might extend patient survival.” 

Lung cancer is the most common cause of cancer-related death in the United States, according to the American Cancer Society, and 85% of lung cancers are classified as NSCLC. Since NSCLCs display variable metabolic features, DeBerardinis Lab researchers sought to find which metabolic features might predict tumor aggressiveness.

The scientists discovered almost all NSCLC tumors incorporated carbon from glucose into the TCA cycle to a greater extent than the lung tissue surrounding the tumor. But patients whose tumors had the highest incorporation had worse outcomes, including much more rapid progression to recurrent or metastatic cancer, and earlier death.

By implanting the same tumors into mice, CRI scientists showed blocking glucose’s ability to feed the TCA cycle suppressed metastatic spread, even though tumors at the site of origin continued to grow.

“We already knew not all tumors used the same metabolic pathways, but it has been difficult to tell which pathways actually matter in terms of cancer mortality,” Dr. DeBerardinis said. “Our study shows isotope tracing, performed in patients with cancer, can identify pathways that predict cancer spread, even far into the future.” 

This DeBerardinis Lab discovery builds on prior research, which showed kidney cancers also rely on flexible mitochondrial metabolism to metastasize. Both studies will guide future research to understand how these metabolic pathways promote cancer progression and whether they can be safely blocked, Dr. DeBerardinis said.

Dr. DeBerardinis has been a Howard Hughes Medical Institute Investigator since 2018. He is Director of the CRI Genetic and Metabolic Disease Program and co-leads the Cellular Networks in Cancer Research Program in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

Dr. DeBerardinis holds the Eugene McDermott Distinguished Chair for the Study of Human Growth and Development and the Philip O’Bryan Montgomery Jr., M.D. Distinguished Chair in Developmental Biology, and is a Sowell Family Scholar in Medical Research.

Other UTSW researchers who contributed to this study include Quyen Do, Ph.D., Assistant Professor of Radiology; Bret Evers, M.D., Ph.D., Assistant Professor of Pathology and Ophthalmology; Thomas P. Mathews, Ph.D., Assistant Professor in CRI and of Pediatrics; John Minna, M.D., Director and Professor of the Hamon Center for Therapeutic Oncology Research, Professor of Internal Medicine and Pharmacology, and co-Leader of the Experimental Therapeutics Research Program in the Simmons Cancer Center; Sean J. Morrison, Director and Professor in CRI and Professor of Pediatrics; Dwight Oliver, M.D., Professor of Pathology; Ashley Solmonson, Ph.D., Assistant Professor in the Cecil H. and Ida Green Center for Reproductive Biology Sciences and of Obstetrics and Gynecology; and John Waters, M.D., Assistant Professor of Cardiovascular & Thoracic Surgery.

Drs. Cai, Kernstine, Minna, Morrison, Oliver, and Waters are members of Simmons Cancer Center.

About CRI

Children’s Medical Center Research Institute at UT Southwestern (CRI) is a joint venture of UT Southwestern Medical Center and Children’s Medical Center Dallas. CRI’s mission is to perform transformative biomedical research to better understand the biological basis of disease. Located in Dallas, Texas, CRI is home to interdisciplinary groups of scientists and physicians pursuing research at the interface of regenerative medicine, cancer biology, and metabolism.

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About UT Southwestern Medical Center

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

DALLAS – Feb. 14, 2025 – Samuel Achilefu, Ph.D., inaugural Chair of Biomedical Engineering at UT Southwestern Medical Center and an internationally recognized leader in the fields of molecular imaging of cancer and nanotherapeutics, has been elected to the National Academy of Engineering (NAE).

Dr. Achilefu, who joined UT Southwestern in February 2022, becomes UTSW’s first faculty member to achieve this prestigious honor, one of the highest professional distinctions bestowed on an engineer. He is also a member of the National Academy of Medicine and a Fellow of the National Academy of Inventors.

Awarded more than 70 U.S. patents, Dr. Achilefu has developed cancer-avid materials and a wearable cancer-imaging goggle system, providing real-time guidance for surgeons to ensure complete removal of cancerous tissue. His seminal work in the use of innovative fluorescent materials for cancer imaging resulted in the clinical translation of a method to identify and treat many cancer types, especially breast tumors. Dr. Achilefu’s research interests also include portable imaging devices and nanotechnology.

Dr. Achilefu, who is also Professor of Biomedical Engineering, Radiology, and in the Harold C. Simmons Comprehensive Cancer Center, helped launch the Texas Instruments Biomedical Engineering and Sciences Building at UT Southwestern in partnership with The University of Texas at Dallas in October 2023. He has grown UTSW’s Biomedical Engineering Department to include 17 primary and 28 secondary faculty members who facilitate basic biomedical research and the detection, diagnosis, and treatment of disease and disability.

“I am deeply grateful to my trainees, staff, colleagues, and family for their support and contributions that have paved the way for my election into the National Academy of Engineering,” Dr. Achilefu said. “I look forward with excitement to the future of biomedical engineering at UT Southwestern.”

Dr. Achilefu has published more than 300 scientific papers. He serves on the Board of Directors for SPIE, the international society for optics and photonics, and has been a member of the National Advisory Council for Biomedical Imaging and Bioengineering. A recipient of more than 20 national and international honors and awards for research excellence and leadership, Dr. Achilefu was the first to receive the Distinguished Investigator Award from the Department of Defense Breast Cancer Research Program.

He is also a fellow of the American Association for the Advancement of Science, the American Institute for Medical and Biological Engineering, the Royal Society of Medicine, the Royal Society of Chemistry, SPIE, and Optica, previously The Optical Society of America.

Before joining UT Southwestern, Dr. Achilefu served more than 20 years in the Mallinckrodt Institute of Radiology at Washington University School of Medicine in St. Louis, where he was the Michel Ter-Pogossian Professor of Radiology, Professor of Medicine, Biomedical Engineering, and Biochemistry & Molecular Biophysics and Director of the Washington University Molecular Imaging Center and the Center for Multiple Myeloma Nanotherapy.

Dr. Achilefu studied chemistry and materials science at the University of Nancy in France before completing postdoctoral training in oxygen transport in biological systems and hematological science at Oxford University in the United Kingdom. 

The National Academy of Engineering, a nonprofit institution, was founded in 1964. Membership honors those who have made outstanding contributions in at least one of the following categories: “engineering practice, research, or education,” “pioneering of new and developing fields of technology, major advancements in traditional fields of engineering, or development/implementation of innovative approaches to engineering education,” or “engineering leadership of one or more major endeavors.” Honorees are elected by their peers.

Dr. Achilefu is one of 128 new U.S. members and 22 international honorees in the NAE’s Class of 2025. His election brings the NAE’s U.S. membership to 2,487 and its international total to 336. Inductees will be honored during the NAE’s annual meeting Oct. 5, 2025, in Washington, D.C.

Dr. Achilefu holds the Lyda Hill Distinguished University Chair in Biomedical Engineering.

About UT Southwestern Medical Center   

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.

DALLAS – Feb. 14, 2025 – An investigational therapy significantly shrank lung cancer tumors that are notoriously resistant to treatment by encouraging an attack from natural killer (NK) cells in an animal model, a study led by UT Southwestern Medical Center researchers shows. The findings, published in the Journal for ImmunoTherapy of Cancer, could lead to new types of immunotherapy that rely on this novel strategy.

Esra Akbay, Ph.D., is Assistant Professor of Pathology and a member of the Development and Cancer Research Program in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

“The approach we studied here could eventually become a viable therapy for patients whose tumors are not responsive to current immunotherapies,” said study leader Esra Akbay, Ph.D., Assistant Professor of Pathology and a member of the Development and Cancer Research Program in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

Immune checkpoint inhibitors (ICIs), a class of anticancer therapies first approved by the Food and Drug Administration in 2011, work by suppressing mechanisms that cancer cells use to inhibit the activity of T cells and thus avoid immune surveillance. By doing so, these drugs enable a patient’s own T cells to fight the cancer. ICIs have revolutionized treatment for many cancers, including non-small cell lung cancer (NSCLC), the most common type of lung cancer.

However, some cancers don’t respond to ICIs, Dr. Akbay explained. These include NSCLC tumors that carry mutations in both the KRAS and LKB1 genes. Patients with this type of cancer, known as KL mutant NSCLC, have limited treatment options if their tumors don’t respond to ICIs.

Searching for a different way to treat these tumors, Dr. Akbay and her colleagues studied NK cells, a type of white blood cell that also fights cancer. Proteins called MICA and MICB, produced on the surface of cells in NSCLC and many other cancer types, can activate NK cells and turn them into cancer killers. KL mutant tumors are especially heavy producers of these proteins. However, cancer cells also shed MICA and MICB into the area surrounding the tumor and the bloodstream. Not only does this shedding reduce the amount of MICA and MICB on cell surfaces available to activate NK cells, Dr. Akbay said, but the proteins that have been shed inactivate NK cells.

To resolve this, she and her colleagues in the Akbay Lab collaborated with Aakha Biologics, a company that makes drugs based on antibodies. These antibodies bind both to antigens (molecules recognized by the immune system) and immune cells. The team designed an antibody, named AHA-1031, that on one side binds to MICA and MICB to prevent them from shedding, and on the other side binds to NK cells to stimulate a phenomenon known as antibody-dependent cellular cytotoxicity (ADCC), which prompts immune cells to kill cancer cells.

Experiments on NSCLC cells growing in petri dishes showed that AHA-1031 bound strongly to MICA and MICB, stabilizing these proteins on the cancer cell surfaces and preventing their shedding. When the researchers introduced NK cells into the cell cultures, results showed that AHA-1031 bound to the surface of cancer cells, causing ADCC. These findings held true for other tumor types that produce MICA and MICB, including pancreatic, colon, ovarian, and prostate cancer cells.

Growth of human NSCLC tumors in mice, even those with KL mutations, was significantly inhibited or prevented with AHA-1031 treatment. This antibody therapy also prevented development of lung metastasis in a mouse model of melanoma.

Together, Dr. Akbay said, these findings suggest that AHA-1031 could have potential as a new type of cancer immunotherapy. If these findings are confirmed in future studies, she added, this antibody therapy could eventually be tested in clinical trials.

Other UTSW researchers who contributed to the study include first author Ryan R. Kowash, Ph.D., graduate student researcher; John D. Minna, M.D., Director of the Hamon Center for Therapeutic Oncology Research, Professor of Internal Medicine and Pharmacology, and co-Leader of the Experimental Therapeutics Research Program in the Simmons Cancer Center; David E. Gerber, M.D., Professor of Internal Medicine and Peter O’Donnell Jr. School of Public Health; Luc Girard, Ph.D., Associate Professor in the Hamon Center for Therapeutic Oncology Research and of Pharmacology; Qing Deng, Ph.D., postdoctoral researcher; and Nusrat U. A. Saleh, M.S., graduate student researcher. Drs. Gerber and Girard are also members of the Simmons Cancer Center.

This study was funded by a Cancer Prevention and Research Institute of Texas Scholar Award (RR160080), National Institutes of Health grants (R01CA276058 and 1R01CA289500), a National Comprehensive Cancer Network Foundation grant, National Cancer Institute training grant (5T32CA124334), National Cancer Institute Cancer Center Support Grant (P30CA142543), a Department of Defense grant (W81XWH-21-1-0856), and a Forbeck Foundation grant.

About UT Southwestern Medical Center   

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.