Background : Largely due to incidental detection, asymptomatic pancreatic cystic le-sions (PCLs) have become prevalent in recent years. Among them, intraductal papillary mucinous neoplasm (IPMN) infrequently advances to pancreatic ductal adenocarci-noma (PDAC). Conservative surveillance versus surgical intervention is a difficult clini-cal decision for both caregivers and PCL patients. Because RNF43 loss- of- function mutations and KRAS gain- of- function mutations concur in a subset of IPMN and PDAC, their biological significance and therapeutic potential should be elucidated. Methods : Pancreatic Rnf43 knockout and Kras activated mice ( Rnf43 ?/? ; Kras G12D ) were generated to evaluate their clinical significance in pancreatic pre- neoplastic ini-tiation and malignant transformation.Results : Loss of Rnf43 potentiated the occurrence and severity of IPMN and PDAC in oncogenic Kras mice. The Wnt/β- catenin signaling pathway was activated in pan-creatic Kras G12D and Rnf43 knockout mice and the PORCN inhibitor LGK974 blocked pancreatic IPMN initiation and progression to PDAC accordingly. Conclusions : Rnf43 is a tumor suppressor in the prevention of pancreatic malignant transformation. This genetically reconstituted autochthonous pancreatic Rnf43 ?/? ; Kras G12D preclinical cancer model recapitulates the pathological process from pan-creatic cyst to cancer in humans and can be treated with inhibitors of Wnt/β- catenin signaling. Since the presence of RNF43 and KRAS mutations in IPMNs predicts future development of advanced neoplasia from PCLs, patients with these genetic anomalies warrant surveillance, surgery, and/or targeted therapeutics such as Wnt/β- catenin inhibitors.