ARID1A Deficiency Promotes Pancreatic Tumorigenesis by Attenuating Mutant KRAS Induced Senescence

ARID1A (AT-rich interacting domain-containing protein 1A) is one of the frequently mutated epigenetic regulators in a wide spectrum of cancers. Recent studies have shown that ARID1A deficiency induces global changes in the epigenetic landscape of enhancers and gene regulations. These complex changes make it challenging to identify the driving mechanisms of ARID1A deficiency in promoting cancer progression. Using a mouse model, we identified the anti-senescence effect of ARID1A deficiency, which promotes the progression of pancreatic intraepithelial neoplasia (PanIN). To identify the underlying mechanism and the players, we profiled the transcriptomes of individual PanIN lesions.  As a result, we observed not only the anti-senescence effect but also the complex trans-differentiation of neoplastic cells. Furthermore, we discovered that significantly upregulated aldehyde dehydrogenase (ALDH) help to inhibit Kras-induced reactive oxygen species (ROS) production and lead to the reduction of the cellular senescence, which results in the accelerated PanIN progression.