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

Date:	December 23, 2025
PMID:	PMC12860476
Category:	N/A
Authors:	Vincent Quoc-Huy Trinh, Katherine E Ankenbauer, Sabrina M Torbit, Christopher P Taranto, Jiayue Liu, Maelle Batardiere, Bhoj Kumar, H Carlo Maurer, Frank Revetta, Zhengyi Chen, Angela R S Kruse, Audra M Judd, Celina Copeland, Jahg Wong, Olivia Ben-Levy, Brenda Jarvis, Monica Brown, Jeffrey W Brown, Koushik Das, Yuki Makino, Jeffrey M Spraggins, Ken S Lau, Parastoo Azadi, Anirban Maitra, Marcus C B Tan, Kathleen E DelGiorno
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 GNAS^R201C 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, GNAS^R201C elevates LacdiNAcs at the expense of pro-tumorigenic acidic Lewis epitopes, inhibiting cancer cell invasion and disease progression. LacdiNAcs and 3'-sulfo-Le^A/C are mutually exclusive and may serve as markers to risk stratify IPMN patients for surgery.

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Acknowledgements:

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, or the National Institute of Health.

The Translational and Basic Science Research in Early Lesions (TBEL) Research Consortia is supported and funded by grants from the National Cancer Institute and the National Institutes of Health under the following award numbers:

Project Number:	Awardee Organization
U54CA274374	Fred Hutchinson Cancer Center
U54CA274375	Houston Methodist Research Institute
U54CA274370	Johns Hopkins University
U54CA274371	UT MD Anderson Cancer Center
U54CA274367	Vanderbilt University Medical Center