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Cellular and Molecular Biology

Functional proteomics of colon cancer Consensus Molecular Subtypes

British Journal of Cancer (2024)Cite this article

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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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Fig. 1: Functional network of the EPIC-XS colon cancer proreins.
Fig. 2: Functional node activities according to CMS groups.
Fig. 3: Significance Analysis of Microarrays of the two CMS2 proteomics-based subtypes.
Fig. 4: Functional node activities comparing the two CMS2 proteomics-based subtypes.
Fig. 5: Flowchart highlighting the main characteristics of each CMS.

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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.

Author information

Authors and Affiliations

  1. Medical Oncology Department, La Paz University Hospital, Paseo de la Castellana 261, 28046, Madrid, Spain

    Jaime Feliu, Daniel Martínez-Pérez, Pablo Pérez-Wert, David Viñal, Nuria Rodríguez-Salas & Ana Custodio

  2. Cátedra UAM-Amgen, Universidad Autónoma de Madrid, Madrid, Spain

    Jaime Feliu

  3. Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII, Madrid, Spain

    Jaime Feliu & Juan Ángel Fresno Vara

  4. Molecular Oncology Lab, La Paz University Hospital-IdiPAZ, Madrid, Spain

    Angelo Gámez-Pozo, Daniel Matamala-Luengo, Rocío López- Vacas, Juan Ángel Fresno Vara & Lucía Trilla-Fuertes

  5. Functional Genomics Center Zurich, Zurich, Switzerland

    Laura Kunz & Antje Dittmann

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  1. Jaime Feliu
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  2. Angelo Gámez-Pozo
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Contributions

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.

Corresponding authors

Correspondence to Jaime Feliu or Lucía Trilla-Fuertes.

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The authors declare no competing interests.

Ethical approval and consent to participate

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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