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Ralph DeBerardinis, MD, Ph.D., (left) is a professor at UT Southwestern’s Children’s Medical Center Research Institute (CRI), the Eugene McDermott Center for Human Growth and Development, and of pediatrics. He is an investigator at the Howard Hughes Medical Institute (HHMI). Divya Bezwada, Ph.D., is a former CRI DeBerardinis Lab investigator who received her Ph.D. in cancer biology from UTSW in 2023.
DALLAS – August 14, 2024 – Unlike the way tumors still in the kidney function, metastatic kidney cancers are highly dependent on mitochondrial metabolism, according to a new study from the Children’s Medical Center Research Institute at UT Southwestern (CRI) published in Nature.
Ralph DeBerardinis, MD, Ph.D., CRI Professor and Howard Hughes Medical Institute (HHMI) investigator, and first author Divya Bezwada, Ph.D., studied different types of kidney cancer in 80 patients at UT Southwestern. They collaborated with surgeons in the UTSW Department of Urology to learn how kidney cancer uses sugar and other nutrients from the blood.
Their most important discovery is that the mitochondrial electron transport chain, a pathway that allows cells to extract energy from nutrients, is much more active in tumors that have metastasized than in tumors that are still growing in the kidney.
“Ultimately, the findings could lead to better treatment options for patients with metastatic cancer or reduce the risk of metastasis in patients with localized cancer at risk of spreading,” said Dr. DeBerardinis. “The challenge now is to understand how these key aspects of mitochondrial metabolism are activated, why they stimulate metastasis, and whether we can safely block them.”
These new findings build on previous CRI discoveries about how certain metabolic activities enable cancer cells to overcome natural barriers to metastasis, Dr. DeBerardinis added.
“For a century, the prevailing notion in cancer biology was that aggressive tumors shut down mitochondrial metabolism to grow and spread. The new research — studying cancer metabolism directly in patients — shows the opposite: Activation of mitochondrial metabolism drives metastasis,” said Dr. DeBerardinis. “Metastasis is the leading cause of cancer-related death in patients with kidney cancer and most other organ cancers. Metastatic tumors are the ones we need to treat most urgently.”
Vitaly Margulis, MD, professor of urology and member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern, led the clinical collaboration.
Vitaly Margulis, MD, professor of urology and member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern, led the clinical collaboration for the study. He is the Paul C. Peters, MD, Chair in Urology at UT Southwestern.
“Most studies of cancer metabolism are done on cells in a petri dish, which may have little relevance to real tumors. This study is one of the few that looks at metabolism where it matters most: in patients,” said Dr. Margulis. “I hope we can use these findings for therapy or early prediction of tumors with high metastatic potential. This would complement the personalized cancer treatment approach we use here at UT Southwestern for each patient with kidney cancer.”
The key technology the CRI scientists used was to intravenously administer nontoxic, labeled forms of several different nutrients to patients during surgical removal of their tumors. Tumor samples were then analyzed to see if the label had moved from the original nutrient to other chemical compounds, a sign that metabolism had occurred. By analyzing multiple nutrients, the team was able to determine that mitochondrial activity was low in tumors that grew in the kidney, but higher when those tumors had metastasized to other organs, including the liver, lungs, and brain.
The researchers’ findings also suggested that mitochondrial activity may promote metastasis. To test this, the scientists used mouse models of kidney cancer that can metastasize to the lungs. In collaboration with Giannicola Genovese, MD, Ph.D. and Luigi Perelli, MD, Ph.D., at the University of Texas MD Anderson Cancer Center, Drs. DeBerardinis and Drs. Bezwada conducted a study that discovered Reduce inhibition of mitochondrial activityS Lung metastases without affecting tumor growth in the kidney. Conversely, activation of mitochondrial activity causes tumors to form metastases significantly more frequently, even though their growth in the kidney remained unaffected.
“This study is an important step toward developing metabolic data that can predict which patients need more aggressive monitoring, surgery or other treatments,” said Dr. Bezwada, a former collaborator in the DeBerardinis Lab. Researchers who received her Ph.D. in cancer biology from UTSW in 2023. “We believe these new insights will help us understand the metabolic needs of kidney cancer cells growing in patients and, more importantly, how these needs change during metastasis.”
Dr. DeBerardinis is the Director of the Genetic and Metabolic Disease Program (GMDP) at CRI, a Professor at the Eugene McDermott Center for Human Growth and Development at UTSW, and a Professor of Pediatrics. He is co-director of the Cellular Networks in Cancer Research Program at the Simmons Cancer Center. He also holds the Joel B. Steinberg, MD Distinguished Chair in Pediatrics, the Robert L. Moody, Sr. Faculty Scholar Award, and the Sowell Family Scholar in Medical Research.
Dr. Bezwada is currently a postdoctoral fellow at Scripps Research.
Other UTSW researchers who contributed to this study include Ling Cai, Ph.D., assistant professor in the Peter O’Donnell Jr. School of Public Health; Feng Cai, Ph.D., assistant professor of CRI and pediatrics; Alan Poole, MD, Ph.D., assistant professor of pediatrics; Yair Lotan, MD, professor of urology; Solomon Woldu, MD, assistant professor of urology; Xiaosong Meng, MD, Ph.D., assistant professor of urology; Jeffrey Cadeddu, MD, professor of urology and radiology; Prashant Mishra, MD, Ph.D., associate professor of CRI and pediatrics; Javier Garcia-Bermudez, Ph.D., assistant professor of CRI and pediatrics; Ivan Pedrosa, MD, Ph.D., vice chair of radiology research and professor of radiology, urology, and the Advanced Imaging Research Center; Payal Kapur, MD, professor of pathology and urology; Kevin Courtney, MD, Ph.D., associate professor of internal medicine; and Craig Malloy, MD, professor in the Advanced Imaging Research Center and of internal medicine and radiology.
Dr. Margulis holds the Paul C. Peters, MD, Chair in Urology. Dr. Lotan holds the Jane and John Justin Distinguished Chair in Urology, in honor of Claus G. Roehrborn, MD. Dr. Meng is a Dedman Family Scholar in Clinical Care. Dr. Cadeddu holds the Ralph C. Smith, MD, Distinguished Chair in Minimally Invasive Urologic Surgery. Dr. Pedrosa holds the Jack Reynolds, MD, Chair in Radiology. Dr. Kapur holds the Jan and Bob Pickens Distinguished Professorship in Medical Sciences, in honor of Jerry Knight Rymer and Annette Brannon Rymer and Mr. and Mrs. WL Pickens. Dr. Malloy holds the Richard A. Lange, MD, Chair in Cardiology.
Dr. Mishra, Garcia-Bermudez, Meng, Kapur and Courtney are members of the Cellular Networks in Cancer Research Program at Simmons Cancer Center. Dr. DeBerardinis, Margulis, Courtney, Kapur, Pedrosa, Lotan, Cadeddu, Woldu and Meng are members of the UTSW Kidney Cancer Specialized Program of Research Excellence (SPORE).
The research was supported by funding from the HHMI Investigator Program and grants from the National Institutes of Health, the National Cancer Institute, the Cancer Prevention and Research Institute of Texas, the Moody Foundation, and Jerry and Emy Lou Baldridge.
About CRI
The Children’s Medical Center Research Institute at UT Southwestern (CRI) is a joint project of UT Southwestern Medical Center and Children’s Medical Center Dallas. CRI’s mission is to conduct groundbreaking biomedical research to better understand the biological basis of disease. Based in Dallas, Texas, CRI is home to interdisciplinary groups of scientists and physicians conducting 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 leading academic medical centers, combines groundbreaking 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, 21 members of the National Academy of Medicine and 14 Howard Hughes Medical Institute investigators. The more than 3,200 full-time faculty members are responsible for groundbreaking medical advances and are committed to rapidly translating science-based research into 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 department cases and manage nearly 5 million outpatient visits annually.
