Children’s Research Institute at UT Southwestern scientists discover kidney cancers rely on mitochondrial metabolism to metastasize

DALLAS – Aug. 14, 2024 – Contrary to how tumors operate while still in the kidney, metastatic kidney cancers rely heavily on mitochondrial metabolism, according to new research from Children’s Medical Center Research Institute at UT Southwestern (CRI) published in Nature.

Studying various types of kidney cancer in 80 UT Southwestern patients, Ralph DeBerardinis, M.D., Ph.D., CRI Professor and Howard Hughes Medical Institute (HHMI) Investigator, and first author Divya Bezwada, Ph.D., collaborated with surgeons from UTSW Department of Urology to track how kidney cancers use sugar and other nutrients from the blood.

Their main discovery is that the mitochondrial electron transport chain, a pathway that allows cells to produce energy from nutrients, is much more active in tumors that have metastasized than in tumors still growing in the kidney.

“Ultimately the findings could lead to better ways to treat patients with metastatic cancer or reduce the risk of metastasis in patients with localized cancers at risk of spreading,” Dr. DeBerardinis said. “The challenge now is to understand how these key aspects of mitochondrial metabolism become activated, why they stimulate metastasis, and whether we can safely block them.”

These new insights build on earlier CRI discoveries about how some metabolic activities allow cancer cells to overcome natural barriers to metastasis, Dr. DeBerardinis added.

“For a century, the dominant idea in cancer biology was that aggressive tumors turn off mitochondrial metabolism in order to grow and spread. The new research – which studied cancer metabolism directly in patients – shows the opposite: Activating mitochondrial metabolism drives metastasis,” Dr. DeBerardinis said. “Metastasis is the most important cause of cancer-related deaths in patients with cancers of the kidney and most other organs. Metastatic tumors are the ones we most need to treat.”

Vitaly Margulis, M.D., Professor of Urology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern, led the clinical collaboration.

“Most cancer metabolism studies are performed on cells in a dish, which might have little relevance to real tumors. This study is one of the few that examines metabolism where it matters most: in patients,” Dr. Margulis said. “I hope we can move these findings forward for therapy or early prediction of tumors with high metastatic potential. That would add to the personalized cancer management approach we use for every patient with kidney cancer here at UT Southwestern.”

The key technology used by CRI scientists involved the intravenous administration of nontoxic, labeled forms of several different nutrients to patients during surgical removal of their tumors. Samples of the tumors were then analyzed to determine whether the label had moved from the original nutrient to other chemical compounds, a sign that metabolism had occurred. Analysis of several nutrients allowed the team to determine that mitochondrial activity was low in tumors growing in the kidney but higher when these tumors had metastasized to other organs, including the liver, lungs, and brain. 

Researchers’ findings further suggested mitochondrial activity might stimulate metastasis. To test this, scientists used mouse models of kidney cancer capable of metastasizing to the lungs. Working with Giannicola Genovese, M.D., Ph.D., and Luigi Perelli, M.D., Ph.D., at The University of Texas MD Anderson Cancer Center, Drs. DeBerardinis and Bezwada led a study that discovered inhibiting mitochondrial activity reduces lung metastasis without affecting tumor growth in the kidney. On the other hand, activating mitochondrial activity causes the tumors to metastasize much more frequently, even though their growth in the kidney was unaffected. 

“This study is an important step to developing metabolic readouts that can predict which patients need more aggressive surveillance, surgery, or other treatments,” said Dr. Bezwada, a former DeBerardinis Lab researcher who received her Ph.D. In Cancer Biology from UTSW in 2023. “We think these new findings will help us understand the metabolic needs of kidney cancer cells growing in patients, and, most importantly, how these needs change during metastasis.”

Dr. DeBerardinis is Director of CRI’s Genetic and Metabolic Disease Program (GMDP), Professor in the Eugene McDermott Center for Human Growth and Development at UTSW and of Pediatrics. He co-leads the Cellular Networks in Cancer Research Program of the Simmons Cancer Center. He also holds the Joel B. Steinberg, M.D. Distinguished Chair in Pediatrics, the Robert L. Moody, Sr. Faculty Scholar Award, and is a Sowell Family Scholar in Medical Research. 

Dr. Bezwada is currently a postdoctoral fellow at Scripps Research.

Other UTSW researchers who contributed to this study are Ling Cai, Ph.D., Assistant Professor in the Peter O’Donnell Jr. School of Public Health; Feng Cai, Ph.D., Assistant Professor in CRI and of Pediatrics; Alan Poole, M.D., Ph.D., Assistant Professor of Pediatrics; Yair Lotan, M.D., Professor of Urology; Solomon Woldu, M.D., Assistant Professor of Urology; Xiaosong Meng, M.D., Ph.D., Assistant Professor of Urology; Jeffrey Cadeddu, M.D., Professor of Urology and Radiology; Prashant Mishra, M.D., Ph.D. Associate Professor in CRI and of Pediatrics; Javier Garcia-Bermudez, Ph.D., Assistant Professor in CRI and of Pediatrics; Ivan Pedrosa, M.D., Ph.D., Vice Chair of Radiology Research and Professor of Radiology, Urology, and in the Advanced Imaging Research Center; Payal Kapur, M.D., Professor of Pathology and Urology; Kevin Courtney, M.D., Ph.D., Associate Professor of Internal Medicine; and Craig Malloy, M.D., Professor in the Advanced Imaging Research Center and of Internal Medicine and Radiology.           

Dr. Margulis holds the Paul C. Peters, M.D., Chair of Urology. Dr. Lotan holds the Jane and John Justin Distinguished Chair in Urology, in Honor of Claus G. Roehrborn, M.D. Dr. Meng is a Dedman Family Scholar in Clinical Care. Dr. Cadeddu holds the Ralph C. Smith, M.D. Distinguished Chair in Minimally Invasive Urologic Surgery. Dr. Pedrosa holds the Jack Reynolds, M.D. Chair in Radiology. 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. Dr. Malloy holds the Richard A. Lange, M.D. Chair in Cardiology.

Drs. Mishra, Garcia-Bermudez, Meng, Kapur and Courtney are members of the Cellular Networks in Cancer Research Program of the Simmons Cancer Center. Drs. DeBerardinis, Margulis, Courtney, Kapur, Pedrosa, Lotan, Cadeddu, Woldu, and Meng are members of the UTSW Kidney Cancer Specialized Program of Research Excellence (SPORE).

Research was supported by HHMI Investigator Program funding as well as grants from the National Institutes of Health, National Cancer Institute, Cancer Prevention and Research Institute of Texas, Moody Foundation, and Jerry and Emy Lou Baldridge.

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, 21 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.