Study examines biological causes of cancer deaths
Tumors invading large blood vessels may be to blame, UTSW researchers say
DALLAS – Oct. 16, 2025 – The ultimate cause of death from cancer may not be metastatic disease, as researchers have long surmised, but an infiltration of tumors into major blood vessels that cause blood clots and multiorgan failure, a one-of-a-kind clinical study led by UT Southwestern Medical Center suggests. These findings, published in Nature Medicine, could spur interventions that extend the lives of patients with advanced cancers.
“The big question we were trying to answer: What kills cancer patients? Why do they die one specific day rather than six months earlier or later?” said Matteo Ligorio, M.D., Ph.D., Assistant Professor of Surgery and in the Harold C. Simmons Comprehensive Cancer Center. Dr. Ligorio led the study along with Kelley Newcomer, M.D., Associate Professor of Internal Medicine at UT Southwestern, and Nicola Aceto, Ph.D., Professor of Molecular Oncology at ETH Zurich in Switzerland.
Cancer claims about 600,000 people in the U.S. each year. However, what actually ends their lives has been a mystery, Dr. Ligorio explained. Although scientists have long proposed that cancer mortality is caused by the spread of tumors throughout the body – a phenomenon known as metastasis – patients often live with metastatic disease for years, suggesting that this may not be what instigates the clinical decline that ultimately leads to death.
Some studies have shown that cancer patients are more likely to develop blood clots in their heart, liver, and lungs, indicating that the cardiovascular system is altered in advanced malignancies. But whether this factor contributes to their demise has been unknown.
To investigate this question, Drs. Newcomer and Ligorio analyzed a retrospective cohort of more than 100 patients with colorectal, lung, ovarian, liver, or pancreatic cancer who had died at William P. Clements Jr. University Hospital and Parkland Health and undergone routine autopsies. Dr. Newcomer then recruited 31 terminally ill patients who were in hospice: 21 with solid tumors and 10 with other conditions. Over the following weeks, she monitored and examined these patients. Dr. Newcomer and Dr. Ligorio’s clinical team also took blood samples whenever the patients reported a significant change in their health status or when their score worsened on an assessment called the Palliative Performance Scale, one of the most commonly used bedside tools to determine the status of patients in palliative care settings.
When these patients died – an average of about 38 days after they were enrolled in the study – Dr. Ligorio performed a modified autopsy on each. While normal autopsy procedures tend not to maintain the integrity of all major blood vessels, his altered protocol preserved them so he could examine their walls and interiors.
The modified autopsies revealed that, unlike the patients who died of other causes, those with cancer typically had tumors penetrating the walls and extending into the interiors of major blood vessels, including the portal vein, inferior vena cava, hepatic veins, and/or abdominal aorta. In several cases where CT scans were available, these vessel-invading growths were present in the weeks or months preceding death, suggesting that such lesions may be detectable on routine imaging.
In addition, blood samples taken during the visits in the follow-up period and analyzed by Dr. Aceto’s team at ETH Zurich revealed a sharp uptick in the number of cancer cells in the bloodstream just before death, strengthening the massive involvement of the cardiovascular system during disease progression.
Together, these findings led Dr. Ligorio to a new theory on what kills cancer patients: When tumors – either primary or metastatic – impinge upon major blood vessels, microscopic pieces of the tumors may break off and join the bloodstream, making blood more likely to clot. Clots that form through this process would restrict blood flow to organs, leading to multiorgan failure that ultimately causes death.
To help validate this idea, researchers examined CT imaging data from 1,250 cancer patients who died that was collected by Dr. Ligorio’s collaborators at the University of Lubeck and the University of Mainz in Germany. Dario Ghersi, M.D., Ph.D., Associate Professor at the University of Nebraska at Omaha, and William Gasper, Ph.D., a graduate student at the University of Nebraska at Omaha at the time of this research, co-led these analyses with Dr. Ligorio, Dr. Newcomer, and Dr. Aceto. They confirmed that most of these patients had tumors infiltrating major blood vessels, supporting this new theory of cancer progression.
“Surgery or radiation to treat tumors approaching large blood vessels could potentially transform how we diagnose, manage, and treat patients with cancers,” Dr. Newcomer said.
Drs. Newcomer and Ligorio thanked the patients and their families who generously agreed to participate in this study to advance the scientific understanding of cancer and support the development of new treatments. They also expressed gratitude to the three hospice organizations — Visiting Nurse Association of Texas, Faith Presbyterian Hospice, and Pathway Hospice — for their collaboration in this clinical study.
Dr. Ligorio and Dr. Newcomer are now designing clinical trials, along with Herbert J. Zeh III, M.D., Chair and Professor of Surgery at UTSW, to test these therapeutic approaches and determine whether targeting tumor-vessel infiltration can substantially extend survival, including in patients with advanced disease.
A full list of contributors and their disclosures can be found in the published study.
This study was funded by grants from the Cancer Prevention and Research Institute of Texas (RR200023), the National Cancer Institute (NCI) (5R37CA242070), the American-Italian Cancer Foundation Post-Doctoral Research Fellowship, the European Research Council (101001652), the strategic focus area of Personalized Health and Related Technologies at ETH Zurich (PHRT-960), the Swiss National Science Foundation (212183), the Swiss Cancer League (KLS-5636-08-2022), the ETH Zurich Lymphoma Challenge (LC-02-22), the ETH Zurich, 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 24 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 13 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.