Plakophilin 3 drives acinar cell transformation and promotes cancer initiation and progression in pancreas.

We discovered that Plakophilin 3 (PKP3) was expressed only at the apical membrane of duct cells in the pancreas, and its expression was induced in acinar-to-ductal metaplasia (ADM), pancreatic intraepithelial neoplasia (PanIN), and pancreatic ductal adenocarcinoma (PDAC) cells. PKP3 was predominantly localized on the cell membrane in ADM and both in the membrane and cytoplasm in PanIN, while PDAC cells expressed PKP3 in the nucleus rather than in the cytoplasm or membrane. PKP3 expression transformed acinar cells into duct-like cells and promoted the malignant behavior of PDAC cells. Mechanistically, PKP3 upregulated FOXM1 expression by inhibiting FOXM1 ubiquitylation. Genetic ablation of PKP3 blocked ADM formation, PanIN and PDAC. Increased PKP3 expression predicted poor survival of patients with PDAC disease. Thus, PKP3 is transformed from a desmosomal protein into an oncogenic molecule that promotes PDAC development through FOXM1 stabilization. This PKP3-FOXM1 signaling axis is a potential target for intervention in early-stage PDAC.