Mitochondrial metabolism in primary and metastatic human kidney cancers

Bezwada, D.; DeBerardinis, R. J.; Lesner, N. P.; Brooks, B.; Vu, H. S.; Wu, Z.; Cai, L.; Kasitinon, S.; Kelekar, S.; Cai, F.; Aurora, A. B.; Patrick, M.; Leach, A.; Ghandour, R.; Zhang, Y.; Do, D.; Sudderth, J.; Dumesnil, D.; House, S.; Rosales, T.; Poole, A. M.; Lotan, Y.; Woldu, S.; Bagrodia, A.; Meng, X.; Cadeddu, J. A.; Mishra, P.; Pedrosa, I.; Kapur, P.; Courtney, K. D.; Malloy, C. R.; Margulis, V.

doi:10.1101/2023.02.06.527285

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bioRxiv · 10.1101/2023.02.06.527285

Mitochondrial metabolism in primary and metastatic human kidney cancers

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Abstract

Most kidney cancers display evidence of metabolic dysfunction1-4 but how this relates to cancer progression in humans is unknown. We used a multidisciplinary approach to infuse 13C-labeled nutrients during surgical tumour resection in over 70 patients with kidney cancer. Labeling from [U-13C]glucose varies across cancer subtypes, indicating that the kidney environment alone cannot account for all metabolic reprogramming in these tumours. Compared to the adjacent kidney, clear cell renal cell carcinomas (ccRCC) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in organotypic slices cultured ex vivo, indicating that suppressed labeling is tissue intrinsic. Infusions of [1,2-13C]acetate and [U-13C]glutamine in patients, coupled with respiratory flux of mitochondria isolated from kidney and tumour tissue, reveal primary defects in mitochondrial function in human ccRCC. However, ccRCC metastases unexpectedly have enhanced labeling of TCA cycle intermediates compared to primary ccRCCs, indicating a divergent metabolic program during ccRCC metastasis in patients. In mice, stimulating respiration in ccRCC cells is sufficient to promote metastatic colonization. Altogether, these findings indicate that metabolic properties evolve during human kidney cancer progression, and suggest that mitochondrial respiration may be limiting for ccRCC metastasis but not for ccRCC growth at the site of origin.

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Bezwada, D., DeBerardinis, R. J., Lesner, N. P., Brooks, B., Vu, H. S., Wu, Z., Cai, L., Kasitinon, S., Kelekar, S., Cai, F., Aurora, A. B., Patrick, M., Leach, A., Ghandour, R., Zhang, Y., Do, D., Sudderth, J., Dumesnil, D., House, S., Rosales, T., Poole, A. M., Lotan, Y., Woldu, S., Bagrodia, A., Meng, X., Cadeddu, J. A., Mishra, P., Pedrosa, I., Kapur, P., Courtney, K. D., Malloy, C. R., Margulis, V.. 2023-02-07. Mitochondrial metabolism in primary and metastatic human kidney cancers. https://doi.org/10.1101/2023.02.06.527285

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