Deficient Rnf43 potentiates hyperactive Kras-mediated pancreatic preneoplasia initiation and malignant transformation  

作　　者：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 

机构地区：[1]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 [2]Institute of Cancer Stem Cell,Dalian Medical University,Dalian,China [3]Institute of Chinese Materia Medica,China Academy of Chinese Medical Sciences,Beijing,China [4]Department of Pathology,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences,Beijing,China [5]MyGenostics Inc.,Beijing,China

出　　处：《Animal Models and Experimental Medicine》2022年第1期61-71,共11页动物模型与实验医学（英文）

基　　金：The National Natural Science Foundation of China(81872287,81730078);the Chinese Academy of Medical Sciences Initiative for Innovative Medicine(2021-1-I2M-018).

摘　　要：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 adenocarcinoma(PDAC).Conservative surveillance versus surgical intervention is a difficult clinical 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 initiation 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 pancreatic 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.

关 键 词：intraductal papillary mucinous neoplasms KRAS pancreatic ductal adenocarcinoma RNF43 Wnt 

分 类 号：R735.9[医药卫生—肿瘤]