Oncogenic KRas-induced Increase in Fluid-phase Endocytosis is Dependent on N-WASP and is Required for the Formation of Pancreatic Preneoplastic Lesions

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• 作者：Clara Lubeseder-Martellato^a ; ^{clara.lubeseder-martellato@tum.de} ; Katharina Alexandrow^a ; Ana Hidalgo-Sastre^a ; Irina Heid^b ; Sophie Luise Boos^a ; ^c ; Thomas Briel^a ; Roland M. Schmid^a ; ^c ; Jens T. Siveke^a ; ^c ; ^d ; ^{j.siveke@dkfz.de}
• 关键词：Oncogenic KRas ; Fluid-phase endocytosis ; Pancreatic ductal adenocarcinoma (PDAC) ; Acinar-to-ductal metaplasia (ADM) ; Acinar epithelial explants ; Neural-Wiskott-Aldrich syndrome protein (N-WASP) ; Mice models
• 刊名：EBioMedicine
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：15
• 期：Complete
• 页码：90-99
• 全文大小：2542 K
• 卷排序：15

文摘

Pancreatic acinar cells harboring KrasG12D have an increased uptake of fluid-phase markers (fluid-phase endocytosis). Pancreatic oncogenic KrasG12D leads to EGFR-dependent sustained fluid-phase endocytosis during acinar-to-ductal metaplasia in vitro. Pancreas-specific deletion of the Neural-Wiskott–Aldrich syndrome protein (N-Wasp) in KrasG12D mice reduces fluid-phase endocytosis and impairs acinar-to-ductal metaplasia.Pancreatic ductal adenocarcinoma (PDAC) is the most lethal among human tumors. Mutated, constitutive active KrasG12D is found in 90% of all human PDACs and is required for tumor initiation that relies on acinar-to-ductal metaplasia. Here we used established genetically engineered mouse models for PDAC and three-dimensional tissue cultures to show that sustained levels of a subtype of endocytosis (fluid-phase endocytosis) is relevant for the development of acinar-to-ductal metaplasia. We also provide some insights into the signaling and cellular processes connected to fluid-phase endocytosis. These data provide a link between oncogenic KRas and sustained FPE during pancreatic cancer initiation.