Scientists Discover Kidney Cancers Rely on Mitochondrial Metabolism to Metastasize

Unlike how tumors function while they are still in the kidney, metastatic kidney cancers rely heavily on mitochondrial metabolism, according to a study from UT Southwestern’s Children’s Medical Center Research Institute (CRI) published in Nature.

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

Their main finding 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 that are still growing in the kidney.

“Ultimately, these findings could lead to better treatments for patients with metastatic cancer or a reduction in the risk of metastasis in patients with localized cancers at risk of spread,” said Dr. DeBerardinis. “The challenge now is to understand how these key aspects of mitochondrial metabolism are activated, why they drive metastasis, and whether we can safely block them.”

This new knowledge builds on CRI’s previous findings about how certain 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 to grow and spread. The new research, which studied 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 have to treat the most.”

Dr. Vitaly Margulis, professor of urology and member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern, led the clinical collaboration.

“Most studies of cancer metabolism are done on cells in a petri dish, which may have little relevance to actual tumors. This study is one of the few to look at metabolism where it matters most: in patients,” Dr. Margulis said.

“I hope we can advance these findings toward therapy or early prediction of tumors with high metastatic potential. This would add to the personalized cancer management approach we use for every kidney cancer patient here at UT Southwestern.”

The key technology used by CRI scientists involved intravenous administration of nontoxic, labeled forms of several different nutrients to patients during surgical removal of their tumors.

Tumor samples were then analyzed to determine whether the marker had passed from the original nutrient to other chemicals, a sign that metabolism had occurred. By analyzing multiple nutrients, the team determined that mitochondrial activity was low in tumors growing in the kidney, but higher when those tumors had metastasized to other organs, including the liver, lungs, and brain.

The researchers’ results also suggest that mitochondrial activity may stimulate metastasis.

To test this theory, the scientists used mouse models of kidney cancer that could metastasize to the lungs. Working with Giannicola Genovese, MD, and Luigi Perelli, MD, MD, of the University of Texas MD Anderson Cancer Center, Drs. DeBerardinis and Bezwada conducted a study that found that inhibiting mitochondrial activity reduced lung metastasis without affecting tumor growth in the kidney.

In contrast, activation of mitochondrial activity leads to much more frequent metastasis of tumors, even if their growth in the kidney is not affected.

“This study is an important step in developing metabolic measures that can predict which patients need more aggressive monitoring, surgery or other treatments,” said Dr. Bezwada, a former researcher in the DeBerardinis lab who received her PhD in cancer biology from UTSW in 2023.

“We believe these new findings will help us understand the metabolic needs of kidney cancer cells growing in patients and, importantly, how these needs change during metastasis.”