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Tumour sampling conditions perturb the metabolic landscape of clear cell renal cell carcinoma

Cissy Yong,Christina Schmidt,Ming Yang,Alex von Kriegsheim,A. Y. Warren,Shubha Anand,J. N. Armitage,Antony C. P. Riddick,Thomas J. Mitchell,Vishal Patil,K. Saeb‐Parsy,S. Vanharanta,Grant D. Stewart,Christian Frezza

Published 2025 in Nature Communications

ABSTRACT

Human isotopic tracer studies are key for in vivo studies of cancer metabolism. Yet, the effects of sampling conditions on the tissue metabolome remain understudied. Here, we perform a 13C-glucose study coupled with metabolomic, transcriptomic, and proteomic profiling in patients with clear cell renal cell carcinoma (ccRCC) to assess the impact of ischaemia on tissues sampled intraoperatively and post-surgical resection, where tissues are exposed to varying degrees of warm ischaemia. Although several metabolic features were preserved, including suppressed TCA cycle activity, ischaemia masked other metabolic phenotypes of ccRCC, such as suppressed gluconeogenesis. Notably, normal kidneys were more metabolically susceptible to ischaemia than the ccRCC tumours. Despite their overall stability, ischaemia caused subtle changes in the proteome and transcriptome. Using orthotopic ccRCC-derived xenografts, we evidenced that prolonged ischaemia disrupted the tissue metabolome stability. Overall, minimising tissue ischaemia is pivotal in accurately profiling cancer metabolism in patient studies. Yong et al. highlight how sampling conditions affect metabolic profile in renal cancer, showing that prolonged ischemic exposure disrupts tissue metabolome stability and masks important phenotypes, such as suppressed gluconeogenesis.

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