ARID1A, a SWI/SNF subunit, is critical to acinar cell homeostasis and regeneration and is a barrier to transformation and epithelial-mesenchymal transition in the pancreas.

Abstract

Here, we evaluate the contribution of AT-rich interaction domain-containing protein 1A (<i>ARID1A</i>), the most frequently mutated member of the SWItch/sucrose non-fermentable (SWI/SNF) complex, in pancreatic homeostasis and pancreatic ductal adenocarcinoma (PDAC) pathogenesis using mouse models. Mice with a targeted deletion of <i>Arid1a</i> in the pancreas by itself and in the context of two common genetic alterations in PDAC, <i>Kras</i> and <i>p53</i>, were followed longitudinally. Pancreases were examined and analysed for proliferation, response to injury and tumourigenesis. Cancer cell lines derived from these models were analysed for clonogenic, migratory, invasive and transcriptomic changes. <i>Arid1a</i> deletion in the pancreas results in progressive acinar-to-ductal metaplasia (ADM), loss of acinar mass, diminished acinar regeneration in response to injury and ductal cell expansion. Mutant <i>Kras</i> cooperates with homozygous deletion of <i>Arid1a</i>, leading to intraductal papillary mucinous neoplasm (IPMN). <i>Arid1a</i> loss in the context of mutant <i>Kras</i> and <i>p53</i> leads to shorter tumour latency, with the resulting tumours being poorly differentiated. Cancer cell lines derived from <i>Arid1a</i>-mutant tumours are more mesenchymal, migratory, invasive and capable of anchorage-independent growth; gene expression analysis showed activation of epithelial-mesenchymal transition (EMT) and stem cell identity pathways that are partially dependent on <i>Arid1a</i> loss for dysregulation. ARID1A plays a key role in pancreatic acinar homeostasis and response to injury. Furthermore, ARID1A restrains oncogenic KRAS-driven formation of premalignant proliferative IPMN. <i>Arid1a</i>-deficient PDACs are poorly differentiated and have mesenchymal features conferring migratory/invasive and stem-like properties.