Mutant GNAS drives a pyloric metaplasia with tumor suppressive glycans in intraductal papillary mucinous neoplasia
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View abstract on PubMed
Summary
This summary is machine-generated.A specific gene mutation (GNASR201C) in pancreatic precancer (IPMN) drives an indolent phenotype by promoting pyloric markers and altering glycans, potentially inhibiting tumor progression.
Area Of Science
- Gastroenterology and Oncology
- Molecular Biology
- Glycobiology
Background
- Intraductal Papillary Mucinous Neoplasms (IPMNs) are precursors to pancreatic ductal adenocarcinoma (PDAC).
- Pancreatic precancer exhibits a transcriptomic program resembling gastric metaplasia.
- This study investigates pyloric markers and molecular drivers in IPMN.
Purpose Of The Study
- To identify pyloric markers in IPMN.
- To pinpoint molecular drivers of the observed transcriptomic program.
- To elucidate the functional role of this program in pancreatic cancer development.
Main Methods
- RNA-sequencing and multiplex immunostaining analyzed pyloric marker expression in patient samples.
- Cell lines and organoids with KrasG12D +/- GNASR201C mutations were subjected to RNA sequencing.
- PyScenic-based regulon analysis identified molecular drivers, validated via RNA-seq, immunostaining, and siRNA knockdown.
- Glycosylation profiling assessed GNASR201C-driven changes, with glycan abundance evaluated in patient samples.
Main Results
- Pyloric markers were detected in human IPMN samples.
- GNASR201C mutation induced this program and an indolent phenotype with altered glycosyltransferases.
- Glycan profiling revealed increased LacdiNAc and decreased pro-tumorigenic Lewis antigens.
- Knockdown of SPDEF or CREB3L1, or chitinase treatment, reduced LacdiNAc and reversed the indolent phenotype.
- LacdiNAc and 3-sulfoLeA/C abundance differentiated low-grade from high-grade IPMN.
Conclusions
- GNASR201C mutation drives an indolent IPMN phenotype by enhancing a differentiated pyloric program via SPDEF/CREB3L1, characterized by specific glycans.
- Mutant GNAS acts as a glycan rheostat, increasing LacdiNAcs while decreasing pro-tumorigenic Lewis epitopes, thus inhibiting cancer cell invasion.
- LacdiNAc and 3-Sulfo-LeA/C are mutually exclusive and may serve as biomarkers for IPMN progression.
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