Mutant GNAS drives a pyloric metaplasia with tumor suppressive glycans in intraductal papillary mucinous neoplasia

Intraductal papillary mucinous neoplasms (IPMNs) are cystic lesions and bona fide precursors of pancreatic ductal adenocarcinoma (PDAC), one of the deadliest solid tumors. Although ∼90% of IPMNs are detected before PDAC forms, markers distinguishing benign from malignant disease are lacking, resulting in an abundance of unnecessary, invasive surgeries. Recent studies show that pancreatic precancer assumes a pyloric phenotype. To identify the regulators of this plasticity, cell lines, organoids, tumors from mouse models of IPMNs, and patient samples underwent multiplex immunostaining, RNA sequencing, glycosylation profiling, and computational analysis. These data revealed that GNAS^R201Cdrives an indolent phenotype in IPMNs by amplifying a differentiated, pyloric phenotype through SPDEF/CREB3L1, which is characterized by distinct glycans. Acting as a glycan rheostat, GNAS^R201Celevates LacdiNAcs at the expense of pro-tumorigenic acidic Lewis epitopes, inhibiting cancer cell invasion and disease progression. LacdiNAcs and 3′-sulfo-Le^A/Care mutually exclusive and may serve as markers to risk stratify IPMN patients for surgery.