TY - JOUR
T1 - Mitochondrial complex I promotes kidney cancer metastasis
AU - Bezwada, Divya
AU - Perelli, Luigi
AU - Lesner, Nicholas P.
AU - Cai, Ling
AU - Brooks, Bailey
AU - Wu, Zheng
AU - Vu, Hieu
AU - Sondhi, Varun
AU - Cassidy, Daniel L
AU - Kasitinon, Stacy Y.
AU - Kelekar, Sherwin
AU - Cai, Feng
AU - Aurora, Arin B
AU - Patrick, McKenzie
AU - Leach, Ashley
AU - Ghandour, Rashed
AU - Zhang, Yuanyuan
AU - Do, Duyen
AU - McDaniel, Phyllis
AU - Sudderth, Jessica A.
AU - Dumesnil, Dennis
AU - House, Sara
AU - Rosales, Tracy I.
AU - Poole, Alan M
AU - Lotan, Yair
AU - Woldu, Solomon
AU - Bagrodia, Aditya
AU - Meng, Xiaosong
AU - Cadeddu, Jeffrey A
AU - Mishra, Prashant
AU - Garcia Bermudez, Javier
AU - Pedrosa, Ivan
AU - Kapur, Payal
AU - Courtney, Kevin D
AU - Malloy, Craig R
AU - Genovese, Giannicola
AU - Margulis, Vitaly
AU - DeBerardinis, Ralph J
PY - 2024/8/14
Y1 - 2024/8/14
N2 - 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.
AB - 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.
M3 - Article
C2 - 39143213
SN - 0028-0836
VL - 633
SP - 923
EP - 931
JO - Nature
JF - Nature
IS - 8031
ER -