Abstract
Background
The Colorectal Cancer Subtyping Consortium established four Consensus Molecular Subtypes (CMS) in colorectal cancer: CMS1 (microsatellite-instability [MSI], Immune), CMS2 (Canonical, epithelial), CMS3 (Metabolic), and CMS4 (Mesenchymal). However, only MSI tumour patients have seen a change in their disease management in clinical practice. This study aims to characterise the proteome of colon cancer CMS and broaden CMS’s clinical utility.
Methods
One-hundred fifty-eight paraffin samples from stage II-III colon cancer patients treated with adjuvant chemotherapy were analysed through DIA-based mass-spectrometry proteomics.
Results
CMS1 exhibited overexpression of immune-related proteins, specifically related to neutrophils, phagocytosis, antimicrobial response, and a glycolytic profile. These findings suggested potential therapeutic strategies involving immunotherapy and glycolytic inhibitors. CMS3 showed overexpression of metabolic proteins. CMS2 displayed a heterogeneous protein profile. Notably, two proteomics subtypes within CMS2, with different protein characteristics and prognoses, were identified. CMS4 emerged as the most distinct group, featuring overexpression of proteins related to angiogenesis, extracellular matrix, focal adhesion, and complement activation. CMS4 showed a high metastatic profile and suggested possible chemoresistance that may explain its worse prognosis.
Conclusions
DIA proteomics revealed new features for each colon cancer CMS subtype. These findings provide valuable insights into potential therapeutic targets for colorectal cancer subtypes in the future.
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Data availability
Proteomics raw data are available in the ProteomeXchange Consortium via the PRIDE (http://www.ebi.ac.uk/pride) partner repository with the data set identifier PXD044935.
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Acknowledgements
We want to particularly acknowledge the patients and the Biobank of Hospital La Paz integrated into the Spanish National Biobanks Network for their collaboration.
Funding
This work was supported by EPIC-XS, project number 823839, funded by the Horizon 2020 programme of the European Union.
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DM-P, PP-W, DV, NR-S, AC, and JF participated in the data curation. RL-V, LK, and AD contributed to the methodology. DM-L, AG-P, JAFV, JF, and LT-F did the formal analyses. JF and LT-F designed the study. LT-F wrote the original draft. JF and AG-P revised the manuscript.
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The work described has been carried out in accordance with the Declaration of Helsinki. Approval for the study was obtained from the La Paz University Hospital Ethical Committee (PI-1019) and informed written consent was obtained for each participant in the study.
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Feliu, J., Gámez-Pozo, A., Martínez-Pérez, D. et al. Functional proteomics of colon cancer Consensus Molecular Subtypes. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02650-6
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DOI: https://doi.org/10.1038/s41416-024-02650-6