Arid1a restrains Kras-dependent changes in acinar cell identity.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 30014851.
- Also identified by DOI 10.7554/eLife.35216 and PMC identifier 6050044.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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<sup>G12D</sup>. Arid1a cooperates with Kras in the adult pancreas as postnatal silencing of Arid1a following sustained Kras<sup>G12D</sup> expression induces rapid and irreversible reprogramming of acinar cells into mucinous PDAC precursor lesions. In contrast, Arid1a silencing during embryogenesis, concurrent with Kras<sup>G12D</sup> 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.
Medical subject headings
- Acinar Cells
- Carcinogenesis
- Cell Differentiation
- Cell Transformation, Neoplastic
- DNA-Binding Proteins
- Morphogenesis
- Nuclear Proteins
- Proto-Oncogene Proteins p21(ras)