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