Deletion of c ore 1 β3galt-specific molecular chaperone (COSMC) in murine intestinal epithelia leads to major alterations in glycocalyx and tumorigenesis

Abstract

Intestinal mucins have extended O-glycans comprised primarily of the common Core 1 O-glycan (Galβ1-3GalNAcα1-Ser/Thr/Tyr) and its modifications. Expression of such glycans is under control of Cosmc (C1GalT1C1) that encodes a key ER molecular chaperone required for formation of active T-synthase, a Golgi enzyme that modifies the Tn antigen (GalNAcα1-Ser/Thr/Tyr – CD175) to generate a Core 1 O-glycan. We previously observed that targeted deletion of Cosmc in murine intestinal epithelial cells (IEC-Cosmc-KO mice) resulted in dysbiosis and alteration of the microbiome. Here we report a detailed description of these mutant mice and find that IEC-Cosmc-KO mice, but not WT mice, express CD175 throughout the intestinal epithelia. CD175 expression is accompanied by loss of glycocalyx, shortening of microvilli, compromised MUC2, thickening of the epithelial layer, as well as generation of high levels of reactive oxygen species. The majority of IEC-Cosmc -/y mice beginning at ∼3 to 9 months spontaneously developed colorectal adenocarcinomas, some with invasive features evidenced by mesenteric metastases, which were potentially associated with activation of TGFβ signaling. Thus, deletion of Cosmc results in expression of CD175 and loss of extended O-glycans in IEC, which is associated with dysregulation of epithelial cell surfaces, leading to spontaneous tumor development.