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

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

Largely due to incidental detection, asymptomatic pancreatic cystic lesions (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. Pancreatic Rnf43 knockout and Kras activated mice (Rnf43 −/−; KrasG12D ) were generated to evaluate their clinical significance in pancreatic pre‐neoplastic initiation and malignant transformation. 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 pancreatic KrasG12D and Rnf43 knockout mice and the PORCN inhibitor LGK974 blocked pancreatic IPMN initiation and progression to PDAC accordingly. Rnf43 is a tumor suppressor in the prevention of pancreatic malignant transformation. This genetically reconstituted autochthonous pancreatic Rnf43 −/−; KrasG12D 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. Pancreatic Rnf43 knockout and Kras activated mice (Rnf43−/− ; KrasG12D ) develop from pancreatic cysts to pancreatic ductal adenocarcinoma which can be blunted by suppression of Wnt/β‐catenin signaling pathway.

在很大程度上由于偶然检测，无症状胰腺囊性病变（PCLs）近年来变得普遍。其中，导管内乳头状黏液性肿瘤（IPMN）很少进展为胰腺导管腺癌（PDAC）。对于医护人员和PCL患者来说，保守监测与手术干预是一个艰难的临床决策。因为RNF43功能丧失突变和KRAS功能获得突变在一部分IPMN和PDAC中同时存在，它们的生物学意义和治疗潜力应该被阐明。 构建了胰腺Rnf43基因敲除和Kras激活小鼠（Rnf43−/−；KrasG12D）以评估它们在胰腺肿瘤前起始和恶性转化中的临床意义。 Rnf43的缺失增强了致癌Kras小鼠中IPMN和PDAC的发生和严重程度。Wnt/β - 连环蛋白信号通路在胰腺KrasG12D和Rnf43基因敲除小鼠中被激活，并且PORCN抑制剂LGK974相应地阻断了胰腺IPMN的起始以及向PDAC的进展。 Rnf43是防止胰腺恶性转化的肿瘤抑制因子。这种基因重组的原位胰腺Rnf43−/−；KrasG12D临床前癌症模型重现了人类从胰腺囊肿到癌症的病理过程，并且可以用Wnt/β - 连环蛋白信号抑制剂进行治疗。由于IPMNs中存在RNF43和KRAS突变预示着PCLs未来会发展为晚期肿瘤，具有这些基因异常的患者需要进行监测、手术和/或靶向治疗，如Wnt/β - 连环蛋白抑制剂。 胰腺Rnf43基因敲除和Kras激活小鼠（Rnf43−/−；KrasG12D）从胰腺囊肿发展为胰腺导管腺癌，这一过程可通过抑制Wnt/β - 连环蛋白信号通路而减缓。