LAUSR

Simple Summary Pancreatic cancer is a highly fatal disease that does not respond well to current cancer therapies. We previously showed that protein kinase C iota (PKCι) is highly expressed in pancreatic cancer, and inhibition of PKCι signaling in human pancreatic cell lines blocks tumor growth. In this study, we used a genetic mouse model to investigate the role of PKCι in pancreatic cellular homeostasis and pancreatic tumorigenesis. We found that inhibition of PKCι expression in the mouse pancreas blocked autophagy, altered infiltration of immune cells, and prevented pancreatic cancer formation. Taken together, these findings reveal a promotive role for PKCι in pancreatic cancer development. Abstract Protein kinase C iota (PKCι) functions as a bonafide human oncogene in lung and ovarian cancer and is required for KrasG12D-mediated lung cancer initiation and progression. PKCι expression is required for pancreatic cancer cell growth and maintenance of the transformed phenotype; however, nothing is known about the role of PKCι in pancreas development or pancreatic tumorigenesis. In this study, we investigated the effect of pancreas-specific ablation of PKCι expression on pancreatic cellular homeostasis, susceptibility to pancreatitis, and KrasG12D-mediated pancreatic cancer development. Knockout of pancreatic Prkci significantly increased pancreatic immune cell infiltration, acinar cell DNA damage, and apoptosis, but reduced sensitivity to caerulein-induced pancreatitis. Prkci-ablated pancreatic acinar cells exhibited P62 aggregation and a loss of autophagic vesicles. Loss of pancreatic Prkci promoted KrasG12D-mediated pancreatic intraepithelial neoplasia formation but blocked progression to adenocarcinoma, consistent with disruption of autophagy. Our results reveal a novel promotive role for PKCι in pancreatic epithelial cell autophagy and pancreatic cancer progression.