Functional proteomics of colon cancer Consensus Molecular Subtypes

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.