Characterizing heterogeneity along EMT and metabolic axes in colorectal cancer reveals underlying consensus molecular subtype-specific trends

Colorectal cancer (CRC) is highly heterogeneous with variable survival outcomes and therapeutic vulnerabilities. A commonly used classification system in CRC is the Consensus Molecular Subtypes (CMS) based on gene expression patterns. However, how these CMS categories connect to axes of phenotypic plasticity and hetero-geneity remains unclear. Here, in our analysis of CMS-specific TCGA data and 101 bulk transcriptomic datasets, we found the epithelial phenotype score to be consistently positively correlated with scores of glycolysis, OXPHOS and FAO pathways, while PD-L1 activity scores positively correlated with mesenchymal phenotype scoring, revealing possible interconnections among plasticity axes. Single-cell RNA-sequencing analysis of pa-tient samples revealed that that CMS2 and CMS3 subtype samples were relatively more epithelial as compared to CMS1 and CMS4. CMS1 revealed two subpopulations: one close to CMS4 (more mesenchymal) and the other closer to CMS2 or CMS3 (more epithelial), indicating a partial EMT-like behavior. Consistent observations were made in single-cell analysis of metabolic axes and PD-L1 activity scores. Together, our results quantify the patterns of two functional interconnected axes of phenotypic heterogeneity - EMT and metabolic reprogramming - in a CMS-specific manner in CRC.

Automated summary

This study investigates the relationship between gene expression patterns and phenotypic plasticity and heterogeneity in colorectal cancer (CRC). The results demonstrate the interconnectedness between different Consensus Molecular Subtypes (CMS) of CRC and specific phenotypes such as epithelial and mesenchymal characteristics. Additionally, the study reveals correlations between metabolic pathways and phenotypic scores, as well as between PD-L1 activity and mesenchymal phenotype. Single-cell RNA sequencing analysis further confirms the heterogeneity of different CMS subtypes. These findings have important implications for understanding CRC heterogeneity and developing targeted therapies.