Faculty, Staff and Student Publications
Publication Date
9-1-2024
Journal
Nature
Abstract
Most kidney cancers are metabolically dysfunctional1-4, but how this dysfunction affects cancer progression in humans is unknown. We infused 13C-labelled nutrients in over 80 patients with kidney cancer during surgical tumour resection. Labelling from [U-13C]glucose varies across subtypes, indicating that the kidney environment alone cannot account for all tumour metabolic reprogramming. Compared with the adjacent kidney, clear cell renal cell carcinomas (ccRCCs) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in ex vivo organotypic cultures, indicating that suppressed labelling is tissue intrinsic. [1,2-13C]acetate and [U-13C]glutamine infusions in patients, coupled with measurements of respiration in isolated human kidney and tumour mitochondria, reveal lower electron transport chain activity in ccRCCs that contributes to decreased oxidative and enhanced reductive TCA cycle labelling. However, ccRCC metastases unexpectedly have enhanced TCA cycle labelling compared with that of primary ccRCCs, indicating a divergent metabolic program during metastasis in patients. In mice, stimulating respiration or NADH recycling in kidney cancer cells is sufficient to promote metastasis, whereas inhibiting electron transport chain complex I decreases metastasis. These findings in humans and mice indicate that metabolic properties and liabilities evolve during kidney cancer progression, and that mitochondrial function is limiting for metastasis but not growth at the original site.
Keywords
Animals, Female, Humans, Male, Mice, Acetates, Carbon Isotopes, Carcinoma, Renal Cell, Cell Respiration, Citric Acid Cycle, Disease Progression, Electron Transport, Electron Transport Complex I, Glucose, Glutamine, Kidney Neoplasms, Mitochondria, NAD, Neoplasm Metastasis, Oxidation-Reduction
DOI
10.1038/s41586-024-07812-3
PMID
39143213
PMCID
PMC11424252
PubMedCentral® Posted Date
8-14-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Nephrology Commons, Oncology Commons