Comprehensive single-cell transcriptome landscape of metastatic colorectal cancer identifies budding-potential cells and their interactions with cancer-associated fibroblasts

Tumor budding is positively associated with colorectal cancer (CRC) metastasis. In this study, we integrated a single-cell transcriptomic dataset of 287 CRC samples to comprehensively illustrate the transcriptomic landscape of metastatic CRC and identified a unique subcluster of tumor epithelial cells associated with tumor budding. This subcluster exhibited high mesothelin (MSLN) expression and was located at the invasive front of CRC. MSLN was confirmed to promote CRC growth and metastasis by in vitro and in vivo models. Also, POSTN⁺ fibroblasts in the CRC microenvironment showed enhanced expression of genes in epithelial-mesenchymal transition and angiogenesis signaling pathways, which wrapped around MSLN⁺ tumor budding cells in the invasive front of CRC. POSTN⁺ fibroblasts may interact with MSLN⁺ budding-potential cells through the ligand-receptor pair POSTN-ITGB5 to promote tumor metastasis. In conclusion, our findings identified the transcriptomic feature of budding-potential cells and revealed the role of crosstalk between MSLN⁺ budding-potential cells and POSTN⁺ fibroblasts in CRC metastasis, which provide new insights into targeting cancer-associated fibroblasts and tumor budding cells in CRC therapy.