A novel comprehensive mucins relevant subtypes predict chemo-responses in colorectal cancer.

[BACKGROUND] Colorectal cancer (CRC) is characterized by aberrant mucin expression, but the full spectrum of mucin profiles and their clinical relevance remain unclear. Here, we developed a novel mucin-based CRC subtyping using multiple datasets to tailor therapeutic strategies.

[METHODS] Mucin-related signatures were used to stratify CRC into four novel mucin-based subtypes: metabolism initiated, inflammatory, immune activated, and progressing. Highly accurate predictions were achieved, with under the curve (AUC) values of 0.977 for PC1 and 0.997 for PC2.

[RESULTS] The novel subtypes demonstrated prognostic potential in predicting CRC patient survival outcomes. We identified interactions between mucin-based subtypes and tumor-associated macrophages (TAMs). Mechanistic research revealed that MUC20 overexpression promoted M2 macrophage-dependent tumor glycolysis and hypoxia. Specifically, M2 phenotype TAMs secreted TNF-α, which enhanced tumor glycolysis and upregulated MUC20 expression in cancer cells. This established a MUC20/glycolysis positive feedback loop that exacerbated hypoxia and aerobic glycolysis in CRC. Additionally, chemotherapy responses in patient organoids were highly matched to these subtypes. Patients in cluster 2 were sensitive to 5-Fu or CPT-11 but potentially resistant to routine FOLFOX treatment.

[CONCLUSION] We identified a novel four mucin-characterized subtypes, which advance precision medicine by refining chemotherapy regimen selection. Our study provides valuable insights for tailoring therapeutic strategies.