Cosmc loss induces truncated O-glycosylation and accelerates Kras-driven pancreatic carcinogenesis.

Aberrant mucin-type O-glycosylation is a common feature of pancreatic ductal adenocarcinoma (PDAC), yet its functional contribution to pancreatic tumorigenesis remains incompletely defined. In particular, whether defective core 1 O-glycan maturation cooperates with oncogenic KRAS during early pancreatic neoplasia has not been fully resolved. Here, we addressed this question by deleting Cosmc (C1galt1c1), the obligate molecular chaperone for T-synthase (C1galt1), in a pancreas-specific Kras-driven mouse model. Analysis of human PDAC tissue microarrays revealed frequent expression of the truncated O-glycan epitopes Tn and sialyl-Tn, supporting the clinical relevance of impaired O-glycan elongation in pancreatic cancer. In vivo, pancreas-specific Cosmc loss in the setting of oncogenic Kras accelerated pancreatic tumor progression, enhanced tissue proliferation, altered acidic mucin-associated glycosylation, and promoted pronounced stromal remodeling. Lectin histochemistry and biochemical analyses confirmed robust accumulation of Tn antigen in Cosmc-deficient pancreatic tumors. To define molecular programs associated with this phenotype, we performed transcriptomic and proteomic profiling of tumor-derived PDAC cell lines together with VVA-enriched glycoproteomic analysis of pancreatic tissues and cell lines. These approaches identified coordinated remodeling of pathways linked to extracellular matrix organization, adhesion, cytoskeletal regulation, stress adaptation, and metabolic reprogramming. Together, these data identify Cosmc-dependent O-glycosylation as a regulator of Kras-driven pancreatic carcinogenesis. Our findings support a model in which truncated O-glycans contribute to PDAC progression in association with remodeling of the tumor glycoproteome and stromal architecture during Kras-driven pancreatic tumor evolution.