SWI/SNF component <i>ARID1A</i> restrains pancreatic neoplasia formation.

Abstract

<i>ARID1A</i> is commonly mutated in pancreatic ductal adenocarcinoma (PDAC), but the functional effects of <i>ARID1A</i> mutations in the pancreas are unclear. Understanding the molecular mechanisms that drive PDAC formation may lead to novel therapies. Concurrent conditional <i>Arid1a</i> deletion and <i>Kras</i> activation mutations were modelled in mice. Small-interfering RNA (siRNA) and CRISPR/Cas9 were used to abrogate <i>ARID1A</i> in human pancreatic ductal epithelial cells. We found that pancreas-specific <i>Arid1a</i> loss in mice was sufficient to induce inflammation, pancreatic intraepithelial neoplasia (PanIN) and mucinous cysts. Concurrent <i>Kras</i> activation accelerated the development of cysts that resembled intraductal papillary mucinous neoplasm. Lineage-specific <i>Arid1a</i> deletion confirmed compartment-specific tumour-suppressive effects. Duct-specific <i>Arid1a</i> loss promoted dilated ducts with occasional cyst and PDAC formation. Heterozygous acinar-specific <i>Arid1a</i> loss resulted in accelerated PanIN and PDAC formation with worse survival. RNA-seq showed that <i>Arid1a</i> loss induced gene networks associated with <i>Myc</i> activity and protein translation. <i>ARID1A</i> knockdown in human pancreatic ductal epithelial cells induced increased MYC expression and protein synthesis that was abrogated with <i>MYC</i> knockdown. ChIP-seq against H3K27ac demonstrated an increase in activated enhancers/promoters. <i>Arid1a</i> suppresses pancreatic neoplasia in a compartment-specific manner. In duct cells, this process appears to be associated with MYC-facilitated protein synthesis.