Arid1a restrains Kras-dependent changes in acinar cell identity

Mutations in members of the SWI/SNF chromatin remodeling family are common events in human 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 pancreas of mice in the setting of oncogenic KrasG12D. Arid1a cooperates with Kras in the adult pancreas as postnatal silencing of Arid1a following sustained KrasG12D expression induces rapid and irreversible reprogramming of acinar cells into mucinous PDAC precursor lesions. In contrast, Arid1a silencing during embryogenesis, concurrent with KrasG12D 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. Identification of the chromatin acessibility changes induced upon dox-inducible Arid1a knockdown in mutant Kras pancreatic epithelial cells: Arid1a-downregulated vs Arid1a-expressing mutant Kras-pancreatic epithelial cells were FACS-sorted from pancreata from p48Cre;RIK;LSL-KrasG12;TRE-shRNA mice (harbouring Arid1a shRNA -6421- or control Renilla shRNA -713-) at day 5 post- doxycycline treatment. Mice were placed on doxycycline diet at 5 weeks of age to induce expression of the indicated shRNAs. Each biological replicate is an independent animal.