Abstract Renal cell carcinoma (RCC) metastatic to the lung and liver remains a lethal disease, with five-year survival rates below ten percent. Employing novel isogenic patient-derived primary and metastatic organoids (PDOs) we identified targetable metabolic adaptations promoting lung and liver metastasis. In vivo metabolic tracing analyses identified distinct metabolite utilization patterns between primary tumors and their matched metastatic lesions. Primary tumors predominantly use glucose derived pyruvate to generate lactate, whereas lung and liver metastatic lesions oxidize it to meet their cellular energetic demands. Reductive glutamine metabolism was predominant in primary tumors and liver metastasis, while oxidative glutamine metabolism was augmented in lung metastasis. Transcriptomic analysis of invasive RCC tumors identified increased expression of Oxphos genes in metastatic tumors relative to non-metastatic tumors. Suppressing electron transport chain (ETC) activity by depleting COX6C or NDUFA4, which are enriched in metastatic lesions significantly reduces metastatic incidence and burden. Residual metastatic cells compensate for ETC inhibition by increasing glycolysis and the reductive carboxylation of glutamine, thereby reducing NADH accumulation and maintaining redox homeostasis. Genetic depletion of key redox regulators, aspartate aminotransferase (GOT1) and malate dehydrogenase (MDH1) attenuates metastatic potential and progression while aspartate and pyruvate supplementation rescued this phenotype. Finally, pharmacological inhibitors targeting both ETC function and glutamine metabolism effectively suppresses metastasis and improve survival in preclinical metastatic PDO models. Collectively, these findings highlight distinct metabolic vulnerabilities of metastatic RCC and support the clinical development of combination metabolic therapies to address this urgent unmet need. Citation Format: Shuhei Kamada, Tuyen T. Dang, Kangsan Kim, Jessica Sudderth, Suvranil Ghosh, Paromita Mitra, Ciara Newman, Dongho Kim, Claire B. Llamas, Qionghua Shen, Chendong Yang, Vanina T. Tcheuyap, Charlotte Small, Brooklyn Jackson, Sophronia Hipsh, Lu Diao, Lauren G. Zacharias, Ashwathi Rajeevan, Tanner Reese, Thomas P. Mathews, Liraz Shmuel-Galia, Prashant Mishra, Qing Zhang, Kevin Dean, Payal Kapur, James Brugarolas, Ralph J. DeBerardinis, Srinivas Malladi. Patient derived organoids identify targetable metabolic adaptations in metastatic ccRCCs abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (5Suppl₂): Abstract nr A028.
Kamada et al. (2026) studied this question.