Mitochondrial metabolism may promote kidney cancer metastasis, new data show

Data recently published in the journal Nature indicate that renal cell carcinoma (RCC) tumors may rely on mitochondrial metabolism to metastasize, contradicting their behavior within the primary kidney and negating previously held theories that mitochondrial complex I is inhibited patients with aggressive tumors.¹

The investigators found that metastatic ccRCC tumors had higher contributions of glucose to the TCA cycle compared with primary ccRCC tumors.

“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,” said senior author Ralph J. DeBerardinis, MD, PhD, in a news release on the findings.² “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.”

The study was conducted by a team of investigators at the University of Texas Southwestern Medical Center in Dallas. Previous work by the group demonstrated that clear cell RCC (ccRCC) tumors have low labelling with [U-¹³C]glucose compared with the adjacent kidney, indicating a low contribution of glucose in the tricarboxylic acid (TCA) cycle, a metabolic pathway.

Data from the current study adds to this finding, indicating that low glucose contribution is an intrinsic characteristic of ccRCC given that cultured ccRCC tissue also demonstrated suppressed glucose contribution. This suppression was also not found across all kidney tumor subtypes, further indicating that it may be a trait specific to ccRCC tumors.

Additionally, the investigators found that metastatic ccRCC tumors had higher contributions of glucose to the TCA cycle compared with primary ccRCC tumors. This finding was consistent in both synchronous metastases and asynchronous metastases and across multiple metastatic sites. According to the authors, this implies “an evolution or selection of mitochondrial function during ccRCC progression in patients.”¹

To further test this finding, the investigators used genetically engineered mouse models of RCC capable of spontaneous metastasis. Findings showed that inhibiting mitochondrial activity reduced metastasis in the lungs without affecting the primary kidney tumor. Conversely, activating mitochondrial activity increased metastatic tumor burden, with no effect to the growth of the primary kidney tumor.

According to the authors, “These data indicate that RCC cells possessing the ability to metastasize need complex I to proliferate and form tumors in the lung, but tolerate inhibition of complex I in the kidney.”¹

In total, the study included 80 patients with kidney cancer who were set to undergo partial or radical nephrectomy. For the study, patients were given a ¹³C-labelled nutrient through a peripheral intravenous line during surgical tumor resection. After surgery (typically 2-3 hours following the start of infusion), tissue samples were obtained for metabolic analysis. Overall, 59 patients with various kidney cancer subtypes were infused with [U-¹³C]glucose and included for analysis, including 37 patients with ccRCC.

Based on these findings, the authors indicate that further research is needed to assess the effect of mitochondrial complex 1 modulation on tumor progression.

“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,” DeBerardinis concluded in the news release.² “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.”

References

1. Bezwada D, Perelli L, Lesner NP, et al. Mitochondrial complex I promotes kidney cancer metastasis. Nature. 2024. doi:10.1038/s41586-024-07812-3

2. Children’s Research Institute at UT Southwestern scientists discover kidney cancers rely on mitochondrial metabolism to metastasize. News release. UT Southwestern Medical Center. Published online and accessed August 14, 2024. https://www.newswise.com/articles/children-s-research-institute-at-ut-southwestern-scientists-discover-kidney-cancers-rely-on-mitochondrial-metabolism-to-metastasize