Arid1a restrains Kras-dependent changes in acinar cell identity

• Published in: eLife Vol. 7
• Main Authors: Livshits, Geulah, Alonso-Curbelo, Direna, Morris, 4th, John P, Koche, Richard, Saborowski, Michael, Wilkinson, John Erby, Lowe, Scott W
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 17-07-2018; eLife Sciences Publications, Ltd
• Subjects: acinar cell; Acinar cells; Acinar Cells - physiology; Adenocarcinoma; Animals; Cancer; Cancer Biology; Carcinogenesis; Carcinoma, Pancreatic Ductal - physiopathology; Cell Differentiation; Cell fate; Cell Transformation, Neoplastic; Chromatin remodeling; Deoxyribonucleic acid; DNA; DNA-Binding Proteins - metabolism; Embryogenesis; Epigenetics; Gene expression; Gene Expression Regulation; Genetic engineering; Genomes; K-Ras protein; Mice; Morphogenesis; Morphology; mouse model; Mutation; Nuclear Proteins - metabolism; Pancreas; pancreas cancer; Pancreatic cancer; plasticity; Proto-Oncogene Proteins p21(ras) - metabolism; RNAi; SWI/SNF; SWI/SNF complex; Tumorigenesis; Tumors; New York; United States > US; Netherlands; mouse; RNAi; mouse model; SWI/SNF; plasticity; cancer biology; pancreas cancer; acinar cell
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.35216

Mutations in members of the SWI/SNF chromatin remodeling family are common events in cancer, but the mechanisms whereby disruption of SWI/SNF components alters tumorigenesis remain poorly understood. To model the effect of loss of function mutations in the SWI/SNF subunit Arid1a in pancreatic ductal adenocarcinoma (PDAC) initiation, we directed shRNA triggered, inducible and reversible suppression of Arid1a to the mouse pancreas in the setting of oncogenic Kras
. Arid1a cooperates with Kras in the adult pancreas as postnatal silencing of Arid1a following sustained Kras
expression induces rapid and irreversible reprogramming of acinar cells into mucinous PDAC precursor lesions. In contrast, Arid1a silencing during embryogenesis, concurrent with Kras
activation, leads to retention of acinar cell fate. Together, our results demonstrate Arid1a as a critical modulator of Kras-dependent changes in acinar cell identity, and underscore an unanticipated influence of timing and genetic context on the effects of SWI/SNF complex alterations in epithelial tumorigenesis.