Tumour sampling conditions perturb the metabolic landscape of clear cell renal cell carcinoma
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 <sup>13</sup>C-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.
Authors
- Christian Frezza (ORCID: https://orcid.org/0000-0002-3293-7397)
- Ming Yang (ORCID: https://orcid.org/0000-0002-7735-7804)
- Kourosh Saeb‐Parsy (ORCID: https://orcid.org/0000-0002-0633-3696)
- Anne Y. Warren (ORCID: https://orcid.org/0000-0002-1170-7867)
- Alex von Kriegsheim (ORCID: https://orcid.org/0000-0002-4952-8573)
- Cissy Yong (ORCID: https://orcid.org/0000-0002-8697-1494)
- Christina Schmidt (ORCID: https://orcid.org/0000-0002-3867-0881)
- Sakari Vanharanta (ORCID: https://orcid.org/0000-0001-5619-7963)
- Grant Duncan Stewart (ORCID: https://orcid.org/0000-0003-3188-9140)
- Shubha Anand
- Thomas J. Mitchell (ORCID: https://orcid.org/0000-0003-0761-9503)
- James N. Armitage
- Vishal Patil (ORCID: https://orcid.org/0000-0001-7805-9705)
- Antony C. P. Riddick
Institutions
- University of Helsinki (FI)
- University of Cambridge (GB)
- Cancer Research UK (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Edinburgh Cancer Research (GB)
- Cancer Research UK Cambridge Center (GB)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- University Hospital Cologne (DE)
- Addenbrooke's Hospital (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-10
- DOI
- https://doi.org/10.1038/s41467-025-65676-1
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00