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

TL;DR

Mutant GNAS in pancreatic cysts promotes a less aggressive form of cancer by altering sugar molecules on cells, which could help avoid unnecessary surgeries.

Contribution

The study identifies GNASR201C as a driver of a tumor-suppressive glycan profile in IPMNs, offering new biomarkers for risk stratification.

Findings

GNASR201C amplifies a pyloric phenotype via SPDEF/CREB3L1 in IPMNs.

LacdiNAcs suppress pro-tumorigenic Lewis epitopes, reducing cancer invasion.

LacdiNAcs and 3′-sulfo-LeA/C are mutually exclusive and may serve as diagnostic markers.

Abstract

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 GNASR201C drives 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, GNASR201C elevates LacdiNAcs at the expense of pro-tumorigenic acidic Lewis epitopes, inhibiting cancer cell invasion and disease progression. LacdiNAcs and 3′-sulfo-LeA/C are mutually exclusive and may serve as markers to risk stratify IPMN patients for surgery.

Trinh et al. show that mutant GNAS promotes pyloric-type differentiation and reprograms glycosylation in pancreatic cystic precancerous lesions. This indolent program slows progression, and glycan signatures distinguish low- from high-grade IPMN.

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