Dataset Information

Mitochondrial metabolism in primary and metastatic human kidney cancers.

ABSTRACT: Most kidney cancers display evidence of metabolic dysfunction^1-4 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.

SUBMITTER: Bezwada D

PROVIDER: S-EPMC9934542 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Mitochondrial metabolism in primary and metastatic human kidney cancers.

Bezwada Divya D Lesner Nicholas P NP Brooks Bailey B Vu Hieu S HS Wu Zheng Z Cai Ling L Kasitinon Stacy S Kelekar Sherwin S Cai Feng F Aurora Arin B AB Patrick McKenzie M Leach Ashley A Ghandour Rashed R Zhang Yuanyuan Y Do Duyen D Sudderth Jessica J Dumesnil Dennis D House Sara S Rosales Tracy T Poole Alan M AM Lotan Yair Y Woldu Solomon S Bagrodia Aditya A Meng Xiaosong X Cadeddu Jeffrey A JA Mishra Prashant P Pedrosa Ivan I Kapur Payal P Courtney Kevin D KD Malloy Craig R CR Margulis Vitaly V DeBerardinis Ralph J RJ

bioRxiv : the preprint server for biology 20230207

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 ...[more]

PMID: 36798172

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Project description:BackgroundSecond primary cancers (SPCs) are increasing due to improving survival in first primary cancers. Previous studies on SPCs in renal cell carcinoma (RCC) have focused on treatment and other risk factors, but data of RCC as an SPC are scarce.ObjectiveIn this study, we want to elucidate the risk for any SPC after RCC, and in reverse order, for RCC as an SPC after any cancer. We additionally consider how family histories influence the risks.Design setting and participantsPatient data were obtained from the Swedish Cancer Registry from years 1990 through 2015, and family data were obtained from the Multigeneration Register.Outcome measurements and statistical analysisWe employed standardized incidence ratios to estimate bidirectional relative risks of subsequent cancer associated with RCC.Results and limitationsWe identified 17 587 RCCs (60% in male patients). The highest increases for SPCs were observed for nervous system hemangioblastoma (HB; 26.8), adrenal (12.09) tumors, and renal pelvic cancer (6.32). In the reverse order, RCC as an SPC, nervous system HB (17.01), and adrenal tumors (15.34) were associated with the highest risks. Risks for many other sites (12 sites and subsites) were increased bidirectionally. For women, a total of seven sites and subsites were increased bidirectionally, and many were shared with men. The only significant sex difference in SPCs was the higher lung cancer risk in women (2.41) than in men (1.28). Patients with a family history of HBs or of prostate, colorectal and lung cancers showed high risks of these cancers as SPCs after RCC. Family history accounted for 30% of prostate cancers after RCC.ConclusionsThe bidirectional study design was able to suggest risk factors for SPCs and offered a clinical take-home message urging to consider strategies for early detection and prevention of SPCs. Readily available information on lifestyle (eg, smoking) and family history (eg, prostate cancer) may reveal targets for risk reduction with prognostic benefits.Patient summaryClose to 10% of kidney cancer patients develop another cancer. The cause for these other cancers may not depend on kidney cancer.

Dataset Information

Mitochondrial metabolism in primary and metastatic human kidney cancers.

Publications

Mitochondrial metabolism in primary and metastatic human kidney cancers.

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