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.

Xian Zhou;Zhichao Sun;Mengdi Zhang;Xiaoyu Qu;Shuhui Yang;Lianmei Wang;Yanling Jing;Li Li;Weiwei Deng;Fangming Liu;Jin Di;Jie Chen;Jian Wu;Hongbing Zhang

State Key Laboratory of Medical Molecular Biology,Department of Physiology,Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing, China;Institute of Cancer Stem Cell,Dalian Medical University,Dalian,China;Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences,Beijing,China;Department of Pathology,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences,Beijing, China;MyGenostics Inc.,Beijing,China

动物模型与实验医学（英文）

[1]Xian Zhou;Zhichao Sun;Mengdi Zhang;Xiaoyu Qu;Shuhui Yang;Lianmei Wang;Yanling Jing;Li Li;Weiwei Deng;Fangming Liu;Jin Di;Jie Chen;Jian Wu;Hongbing Zhang-.Deficient Rnf43 potentiates hyperactive Kras-mediated pancreatic preneoplasia initiation and malignant transformation)[J].动物模型与实验医学（英文）,2022(01):61-71

Rnf43,preneoplasia,adenocarci,PORCN,LGK974,recapitulates,IPMNs

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