Metabolism and malignancy
A few years ago, Dr. Ralph DeBerardinis began seeing lab results that challenged long-standing scientific thinking about how cancer cells grow.
The UT Southwestern pediatrician and cancer researcher’s tests showed that lung cancer tumors could use a number of nutrients for food – including lactate, formed by the breakdown of glucose (sugar) and long considered just a waste product.
His findings flew in opposition to the so-called Warburg effect. The 1924 theory put forward by the Nobel Prize-winning German scientist and physician Dr. Otto Heinrich Warburg postulated that cancer cells generate energy by breaking down glucose. The hallmarks of this process, according to Dr. Warburg, are rapid glucose uptake, reduced pyruvate oxidation, and secretion of lactate as a waste product.
Dr. DeBerardinis, Professor at the Children’s Medical Center Research Institute at UT Southwestern (CRI) and Chief of the Division of Pediatric Genetics and Metabolism at UT Southwestern, admits pausing at the findings. “I’ve been surprised by many of these results,” he says. “I had a bit of a gut check when we started writing about lactate as a fuel for tumors. But we have to trust the data.”
Challenging a long-held theory
The results created a stir. But Dr. DeBerardinis comes armed with a reputation that can stand up to scientific surprises.
He is one of the world’s leading researchers who investigate how tumors metabolize nutrients in studies done directly in patients. At UT Southwestern, he has also become the metaphorical hub from which dozens of other research projects radiate.
“Ralph is definitely one of the world’s foremost experts in this area,” says Dr. Kathryn O’Donnell, an Assistant Professor of Molecular Biology at UTSW. “Everyone who is working on a cancer metabolism project here is connected to Ralph.”
Dr. O’Donnell studies an enzyme she discovered on the surface of lung cancer cells that helps move lactate out of the cells.
An edge with technology
Only over the past 20 years has UT Southwestern’s novel focus on cancer metabolism become possible, Dr. DeBerardinis says.
With the emergence of nonradioactive isotopes such as carbon-13, doctors can now safely inject patients with tracers to track what happens as glucose, for example, makes its way through cancer cells. A patient undergoing a tumor biopsy, or perhaps surgical removal of a tumor, can be injected with glucose combined with this harmless isotope tracer. Then, immediately after the surgery, researchers can examine the cancer samples to see what path the sugar took as it was used by cells within the tumor or the surrounding noncancerous tissue.
This new ability, combined with major advances in the machinery used to analyze metabolites, can greatly accelerate discoveries in cancer metabolism, Dr. DeBerardinis says. Today’s mass spectrometers, for example, can analyze hundreds of metabolites nearly simultaneously.
“Because of the use of this technology, we can study cancer metabolism directly in humans with many types of cancer,” says Dr. Carlos Arteaga, Director of the Harold C. Simmons Comprehensive Cancer Center and Associate Dean of Oncology Programs at UT Southwestern. The hope, he says, is to find a way to cut off the pathways that feed the cancer – or to identify new metabolic vulnerabilities that can be targeted with drugs to slow or stop the cancer’s growth.
“It was not until relatively recently that this approach has been done directly in cancer patients,” Dr. Arteaga says. “UT Southwestern is leading the way in this area of cancer discovery and translational research.”
In fact, Dr. DeBerardinis says, UT Southwestern has the most advanced program in the world using machines for in-patient metabolism tracking in cancer – with faculty members skilled at using this technology. Another UT Southwestern advantage for cancer metabolism research is its collaborative culture.
The patient advantage
For Dr. DeBerardinis’ 2016 and 2017 Cell papers, Dr. Kemp Kernstine, Professor of Cardiovascular and Thoracic Surgery at UTSW, recruited the needed lung cancer patients and became an essential partner in the work.
“UT Southwestern has the most advanced program in the world using machines for in-patient metabolism tracking in cancer.”
Dr. DeBerardinis’ efforts to study cancer metabolism in living patients – rather than in cells grown in a petri dish or in mice – turned UT Southwestern into a leader in this field. This work also allowed him to challenge Dr. Warburg’s theory after almost 100 years.
Using isotope-illuminated pathways in tissue samples from living cancer patients makes it possible to track metabolism and the metabolites produced, Dr. DeBerardinis explains. This provides an advantage over Dr. Warburg’s original studies, which were performed only after tumor tissue was removed from the body. This approach may have produced a picture of metabolism that bore little resemblance to how the tumors actually functioned inside the body, he says.
However, some cancers – notably kidney cancer – do seem to adhere to the Warburg effect, Dr. DeBerardinis adds. He referred to a 2018 Cell Metabolism study from UT Southwestern that compared kidney tumor metabolism with metabolism in the normal kidney and with tumors growing in the human brain and lung.
Multiple cancer metabolism angles
Dr. DeBerardinis arrived at UT Southwestern in 2008 from the University of Pennsylvania, where he earned M.D. and Ph.D. degrees and worked under Dr. Craig B. Thompson, a leader in cancer metabolism who is now President and CEO of Memorial Sloan Kettering Cancer Center in New York.
Dr. O’Donnell, who received her Ph.D. in genetics from Johns Hopkins School of Medicine, came to UT Southwestern in 2011. At Johns Hopkins, she had worked with Dr. Chi Van Dang, known for his research into how the MYC oncogene (or cancer-causing gene) reprograms cellular energy metabolism.
During her doctoral studies, Dr. O’Donnell investigated how MYC regulates iron metabolism. Once at UT Southwestern, she began performing genetic screens to identify new genes that can convert precancerous lung cells into malignant ones during which she noticed a gene that makes an enzyme expressed at increased levels in human squamous cell lung cancers.
As she studied the enzyme, called transmembrane serine protease 11B, or TMPRSS11B, she realized it helps lung cancer cells secrete lactate. Her 2018 study, co-authored with Dr. DeBerardinis and published in Cell Reports, describes how TMPRSS11B sits on the cancer cell membrane and encourages lactate to move out of the cell. When TMPRSS11B is inhibited, lactate can’t exit as efficiently and tumor growth is reduced, she says. Because lactate is also believed to suppress the immune system, Dr. O’Donnell is now investigating whether the enzyme lessens the body’s ability to attack tumors.
Meanwhile, Assistant Professor of Molecular Biology Dr. Jenna Jewell consults with Dr. DeBerardinis as she studies a protein complex called mTORC1 that controls protein synthesis. Her lab investigates how glutamine – an amino acid used by cancer cells to fuel cell growth and proliferation – signals to mTORC1. Her reports in Science in 2015 and in Development last year examine this connection.
“Cancer is incredibly complicated. We’re only going to advance the field if we have multiple people really attacking the same problem.”
She continues to collaborate with Dr. DeBerardinis – who is interested in how glutamine regulates cancer cell growth – to figure out how this protein sends messages to mTORC1. Identifying new components in the mTORC1 complex used to signal the cancer cell to grow and proliferate “will be significant in identifying new therapeutic targets to treat cancer,” Dr. Jewell says.
Meanwhile, dozens of other UT Southwestern researchers approach cancer metabolism from different directions or collaborate on projects.
“Now is a great time to be working in metabolism,” says Dr. DeBerardinis, who is also a Howard Hughes Medical Institute Investigator. “I would love to have other centers try to do this. Cancer is incredibly complicated. We’re only going to advance the field if we have multiple people really attacking the same problem.”
Dr. Arteaga holds The Lisa K. Simmons Distinguished Chair in Comprehensive Oncology.
Dr. DeBerardinis holds the Joel B. Steinberg, M.D. Chair in Pediatrics, and is a Sowell Family Scholar in Medical Research.
Dr. Kernstine holds the Robert Tucker Hayes Foundation Distinguished Chair in Cardiothoracic Surgery.