Healthcare (Commonwealth Union) – A new study from the Children’s Medical Center Research Institute at UT Southwestern (CRI), published in Nature, reveals that metastatic kidney cancers depend significantly on mitochondrial metabolism, unlike tumors that remain in the kidney.
Ralph DeBerardinis, M.D., Ph.D., a CRI Professor and Investigator at the Howard Hughes Medical Institute (HHMI), along with lead author Divya Bezwada, Ph.D., and surgeons from the UTSW Department of Urology examined various kidney cancer types in 80 UT Southwestern patients. Their research focused on how kidney cancers utilize sugar and other blood-borne nutrients.
Their key finding is that the mitochondrial electron transport chain—a process enabling cells to generate energy from nutrients—is much more active in metastatic tumors than in those confined to the kidney.
Dr. DeBerardinis stated that these findings could eventually pave the way for improved treatments for patients with metastatic cancer or help lower the risk of metastasis in those with localized cancers prone to spreading. He further pointed out that the next challenge is to unravel how these crucial aspects of mitochondrial metabolism are triggered, why they promote metastasis, and whether they are able to safely inhibit them.
He also noted that these findings build upon previous CRI research showing how certain metabolic processes enable cancer cells to bypass natural barriers to metastasis.
Dr. DeBerardinis further stated that for the past century, the prevailing belief in cancer biology was that aggressive tumors shut down mitochondrial metabolism to facilitate their growth and spread. However, recent research that directly examined cancer metabolism in patients reveals the opposite: activating mitochondrial metabolism actually drives metastasis.
“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.”
Dr. Vitaly Margulis, Professor of Urology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern, spearheaded the clinical collaboration.
Dr. DeBerardinis added that these new findings expand on previous CRI research, which uncovered how certain metabolic activities enable cancer cells to bypass natural barriers to metastasis.”
“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,” explained Dr. Margulis. “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 primary technique employed by CRI scientists involved intravenously administering non-toxic, labeled variants of various nutrients to patients during the surgical excision of their tumors. Afterward, tumor samples were examined to determine if the label had shifted from the initial nutrient to other chemical compounds, indicating that metabolism had taken place. By analyzing several nutrients, the team found that mitochondrial activity was lower in tumors growing in the kidney but higher when these tumors had spread to other organs, such as the liver, lungs, and brain.
The researchers’ findings also implied that mitochondrial activity might promote metastasis. To investigate this, scientists used mouse models of kidney cancer with the ability to metastasize to the lungs. Collaborating with Drs. Giannicola Genovese and Luigi Perelli at The University of Texas MD Anderson Cancer Center, Drs. DeBerardinis and Bezwada carried out research revealing that inhibiting mitochondrial activity reduces lung metastasis without affecting the growth of the kidney tumor. Conversely, activating mitochondrial activity led to a significant increase in metastasis, even though the kidney tumor’s growth remained unchanged.
Dr. Bezwada indicated that the study is a crucial advancement toward creating metabolic indicators that can help identify patients who require more intensive monitoring, surgery, or other treatments.
The greater role of metabolism in cancer has also been repeatedly demonstrated in studies conducted by Professor Thomas Seyfried.
