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More than acinar identity? A novel cystic phenotype suggests broader roles for NR5A2 in pancreatic cancer †
Author(s) -
Aney Katherine J,
Nissim Sahar
Publication year - 2021
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5619
Subject(s) - kras , pancreatic intraepithelial neoplasia , liver receptor homolog 1 , biology , phenotype , cancer research , acinar cell , pancreatic cancer , transcription factor , nuclear receptor , cancer , pancreas , endocrinology , genetics , gene , colorectal cancer
The prognosis for pancreatic ductal adenocarcinoma (PDAC) remains dismal. Multiple genome‐wide association studies (GWAS) have implicated the nuclear receptor NR5A2 in modulating PDAC risk, but mechanisms for this association are not understood. NR5A2 is a transcription factor that maintains acinar cell identity, and heterozygous loss of Nr5a2 in mice accelerates oncogenic Kras ‐driven formation of pancreatic intraepithelial neoplasia (PanIN), a PDAC precursor derived from acinar cells. In a recent issue of The Journal of Pathology , Cobo et al characterize a novel mouse model that uses Ptf1a:Cre to drive oncogenic Kras as well as heterozygous Nr5a2 inactivation. In addition to the expected PanIN lesions, these mice exhibited a surprising phenotype: large pancreatic cystic lesions which have not been previously reported. Comparing expression of oncogenic Kras and heterozygous Nr5a2 in various mouse models reveals several possible explanations for these cystic lesions. Importantly, these differences across mouse models suggest that NR5A2 may contribute to PDAC precursors in ways beyond its previously characterized acinar cell‐autonomous role. These observations highlight that pathways implicated by GWAS may have roles in unexpected cell types, and an understanding of these roles will be critical to guide new preventive and treatment strategies for PDAC. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.