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

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.

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.

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.

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.