Functional proteomics of colon cancer Consensus Molecular Subtypes
Related Experiment Video
Updated: Jun 30, 2025
A Streamlined Approach for Mass Spectrometry-Based Proteomics Using Selected Tissue Regions
Published on: April 18, 2025
Jaime Feliu1,2,3, Angelo Gámez-Pozo4, Daniel Martínez-Pérez5
1Medical Oncology Department, La Paz University Hospital, Paseo de la Castellana 261, 28046, Madrid, Spain. jaimefeliu@hotmail.com.
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.
Insights
Proteomics analysis of colorectal cancer subtypes (CMS) revealed distinct protein profiles for CMS1, CMS3, and CMS4, offering new therapeutic targets. CMS2 showed heterogeneity, with two subtypes identified, impacting prognosis and treatment strategies.
Area of Science:
- Oncology
- Proteomics
- Molecular Biology
Background:
- The Colorectal Cancer Subtyping Consortium defined four Consensus Molecular Subtypes (CMS) in colorectal cancer: CMS1 (immune), CMS2 (canonical), CMS3 (metabolic), and CMS4 (mesenchymal).
- Clinical management has only been significantly impacted for microsatellite-instability (MSI) tumors.
- This study aimed to characterize the proteome of colon cancer CMS subtypes to enhance their clinical utility.
Purpose of the Study:
- To comprehensively characterize the proteome of each colon cancer Consensus Molecular Subtype (CMS).
- To identify novel protein-based features for each CMS.
- To explore the potential for broadening the clinical utility of CMS classification.
Main Methods:
- Analysis of 158 paraffin-embedded stage II-III colon cancer samples from patients treated with adjuvant chemotherapy.
- Utilized Data-Independent Acquisition (DIA)-based mass-spectrometry proteomics for comprehensive protein profiling.
Main Results:
- CMS1 showed overexpression of immune and glycolytic proteins, suggesting immunotherapy and glycolytic inhibitor potential.
- CMS3 exhibited overexpression of metabolic proteins.
- CMS2 displayed a heterogeneous protein profile with two distinct subtypes identified, differing in characteristics and prognosis.
- CMS4 presented a distinct profile with overexpression of angiogenesis, extracellular matrix, and complement proteins, indicating a high metastatic potential and possible chemoresistance.
Conclusions:
- Data-Independent Acquisition (DIA) proteomics has unveiled novel proteomic features for each colon cancer CMS subtype.
- These findings offer valuable insights into potential therapeutic targets for distinct colorectal cancer subtypes.
- The proteomic characterization provides a foundation for refining treatment strategies based on CMS classification.
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