Faculty, Staff and Student Publications

Language

English

Publication Date

1-2-2026

Journal

Journal of Clinical Investigation

DOI

10.1172/JCI194395

PMID

41480763

PMCID

PMC12721884

PubMedCentral® Posted Date

1-1-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Pancreatic ductal adenocarcinoma (PDAC) occurs as a complex, multifaceted event driven by the interplay of tumor-permissive genetic mutations, the nature of the cellular origin, and microenvironmental stress. In this study, using primary human pancreatic acinar 3D organoids, we performed a CRISPR-KO screen targeting 199 potential tumor suppressors curated from clinical PDAC samples. Our data revealed significant enrichment of a list of candidate genes, with neurofibromatosis type 2 associated gene (NF2) emerging as the top target. Functional validation confirmed that loss of NF2 promoted the transition of PDAC to an invasive state, potentially through extracellular matrix modulation. NF2 inactivation was found to enhance PDAC cell fitness under nutrient starvation. This adaptation not only reinforced the oncogenic state but also conferred therapeutic resistance. Additionally, we found that NF2 loss was associated with fibroblast heterogeneity and cancer-stroma communication in tumor evolution. These findings establish NF2 as a critical tumor suppressor in PDAC and uncover its role in mediating nutrient adaptation and drug resistance. Importantly, this study provides additional insights into drug resistance mechanisms and potential therapeutic targets in PDAC.

Keywords

Humans, Carcinoma, Pancreatic Ductal, Pancreatic Neoplasms, Acinar Cells, Neurofibromin 2, Cell Transformation, Neoplastic, Tumor Microenvironment, Mice, Gastroenterology, Genetics, Oncology, Cancer, Therapeutics, Tumor suppressors

Published Open-Access

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