Single-cell analysis identifies dysregulated cell type-specific gene programs and intercellular crosstalk underlying...

Colorectal cancer, a leading cause of cancer-related mortality, arises from the stepwise accumulation of genetic alterations in colonic epithelial cells, accompanied by dynamic remodeling of the tumor microenvironment. While the adenoma-carcinoma sequence is widely recognized, the cell type-specific gene programs and their interactions with the tumor microenvironment that drive malignant transformation remain poorly understood. In this study, we analyzed single-nucleus data from colorectal carcinoma and matched unaffected tissues, revealing dysregulated gene programs at the level of individual cell types. In epithelial cells, we identified two activated modules linked to enhanced stemness and two repressed modules associated with apoptosis and chronic inflammatory signaling. Transcription factors analysis highlighted CEBPB and RUNX1 as key activated regulators, while FOXP1 and POU5F1 were repressed in cancerous cells. Further investigation of intercellular communication uncovered disrupted crosstalk between epithelial cells and tumor microenvironment components, which may underlie these gene program alterations. Additionally, we observed functional reprogramming within the tumor microenvironment, including extracellular matrix remodeling by stromal fibroblasts and impaired B-cell-mediated immunity. Together, these findings improve our understanding of the molecular and cellular mechanisms driving colorectal tumorigenesis and may bring new opportunities for the development of therapeutic strategies.