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<sup>R201C</sup> 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<sup>R201C</sup> elevates LacdiNAcs at the expense of pro-tumorigenic acidic Lewis epitopes, inhibiting cancer cell invasion and disease progression. LacdiNAcs and 3'-sulfo-Le<sup>A/C</sup> are mutually exclusive and may serve as markers to risk stratify IPMN patients for surgery.

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Publication Details

Journal
Cell Reports
Published
2025-12-01
DOI
https://doi.org/10.1016/j.celrep.2025.116684
Primary Topic
Glycosylation and Glycoproteins Research
Type
article
Field-Weighted Citation Impact
0.00
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article

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

Frank Revetta, Olivia Ben‐Levy, Brenda Jarvis, Vincent Quoc‐Huy Trinh et al.
Cell Reports
Glycosylation and Glycoproteins Research
article

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

Frank Revetta, Olivia Ben‐Levy, Brenda Jarvis, Vincent Quoc‐Huy Trinh, H. Carlo Maurer, Koushik K. Das, Jahg Wong, Katherine E. Ankenbauer, Angela Kruse, Anirban Maitra, Yuki Makino, Bhoj Kumar, Jeffrey M. Spraggins, Ken S. Lau, Marcus Tan, Parastoo Azadi, Kathleen E. DelGiorno, Audra M. Judd, Jeffrey W. Brown, Maëlle Batardière, Sabrina M. Torbit, Zheng‐Yi Chen, Jiayue Liu, Monica Brown, Celina Copeland, C. Taranto
article en

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<sup>R201C</sup> 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<sup>R201C</sup> elevates LacdiNAcs at the expense of pro-tumorigenic acidic Lewis epitopes, inhibiting cancer cell invasion and disease progression. LacdiNAcs and 3'-sulfo-Le<sup>A/C</sup> are mutually exclusive and may serve as markers to risk stratify IPMN patients for surgery.

Cell ReportsVol. 44(12)
The University of Texas MD Anderson Cancer Center (US), University of Georgia (US), Vanderbilt University (US), Washington University in St. Louis (US), TUM Klinikum (DE), Institute for Research in Immunology and Cancer (CA), Centre Hospitalier de l’Université de Montréal (CA), Vanderbilt University Medical Center (US)
Openalex Percentile: Top 64%
Glycosylation and Glycoproteins Research
DOIOpen Access PDFOpenAlex
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