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

Cissy Yong, Christina Schmidt, Ming Yang, Alexander Von Kriegsheim, Anne Y. Warren, Shubha Anand, James N. Armitage, Antony C. P. Riddick, Thomas J. Mitchell, Vishal Patil, Kourosh Saeb-Parsy, Sakari Vanharanta, Grant D. Stewart and Christian Frezza ()
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Cissy Yong: Cambridge University Hospitals NHS Foundation Trust (CUHFT)
Christina Schmidt: Institute for Metabolomics in Ageing
Ming Yang: Institute for Metabolomics in Ageing
Alexander Von Kriegsheim: Institute of Genetics and Molecular Medicine
Anne Y. Warren: CUHFT
Shubha Anand: CRUK Cambridge Cancer Centre
James N. Armitage: Cambridge University Hospitals NHS Foundation Trust (CUHFT)
Antony C. P. Riddick: Cambridge University Hospitals NHS Foundation Trust (CUHFT)
Thomas J. Mitchell: Cambridge University Hospitals NHS Foundation Trust (CUHFT)
Vishal Patil: CUHFT
Kourosh Saeb-Parsy: University of Cambridge
Sakari Vanharanta: University of Helsinki
Grant D. Stewart: Cambridge University Hospitals NHS Foundation Trust (CUHFT)
Christian Frezza: Institute for Metabolomics in Ageing

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-65676-1

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