title: Oncogenic KRas-induced Increase in Fluid-phase Endocytosis is Dependent on N-WASP and is Required for the Formation of Pancreatic Preneoplastic Lesions.
abstract: Fluid-phase endocytosis is a homeostatic process with an unknown role in tumor initiation. The driver mutation in pancreatic ductal adenocarcinoma (PDAC) is constitutively active KRasG12D, which induces neoplastic transformation of acinar cells through acinar-to-ductal metaplasia (ADM). We have previously shown that KRasG12D-induced ADM is dependent on RAC1 and EGF receptor (EGFR) by a not fully clarified mechanism. Using three-dimensional mouse and human acinar tissue cultures and genetically engineered mouse models, we provide evidence that (i) KRasG12Dleads to EGFR-dependent sustained fluid-phase endocytosis (FPE) during acinar metaplasia; (ii) variations in plasma membrane tension increase FPE and lead to ADM in vitro independently of EGFR; and (iii) that RAC1 regulates ADM formation partially through actin-dependent regulation of FPE. In addition, mice with a pancreas-specific deletion of the Neural-Wiskott-Aldrich syndrome protein (N-WASP), a regulator of F-actin, have reduced FPE and impaired ADM emphasizing the in vivo relevance of our findings. This work defines a new role of FPE as a tumor initiating mechanism.
authors.affiliation: Clinic and Polyclinic for Internal Medicine II, Klinikum Rechts der Isar, Technical University of Munich, Germany. Electronic address: clara.lubeseder-martellato@tum.de.
authors.forename: Clara
authors.initials: C
authors.lastname: Lubeseder-Martellato
authors.affiliation: Clinic and Polyclinic for Internal Medicine II, Klinikum Rechts der Isar, Technical University of Munich, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Alexandrow
authors.affiliation: Clinic and Polyclinic for Internal Medicine II, Klinikum Rechts der Isar, Technical University of Munich, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Hidalgo-Sastre
authors.affiliation: Institute of Radiology, Klinikum Rechts der Isar, Technical University of Munich, Germany.
authors.forename: Irina
authors.initials: I
authors.lastname: Heid
authors.affiliation: Clinic and Polyclinic for Internal Medicine II, Klinikum Rechts der Isar, Technical University of Munich, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center, DKFZ, Heidelberg, Germany.
authors.forename: Sophie Luise
authors.initials: SL
authors.lastname: Boos
authors.affiliation: Clinic and Polyclinic for Internal Medicine II, Klinikum Rechts der Isar, Technical University of Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Briel
authors.affiliation: Clinic and Polyclinic for Internal Medicine II, Klinikum Rechts der Isar, Technical University of Munich, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center, DKFZ, Heidelberg, Germany.
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.affiliation: Clinic and Polyclinic for Internal Medicine II, Klinikum Rechts der Isar, Technical University of Munich, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center, DKFZ, Heidelberg, Germany; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK), Partner Site Essen, West German Cancer Center, University Hospital Essen, Germany. Electronic address: j.siveke@dkfz.de.
authors.forename: Jens T
authors.initials: JT
authors.lastname: Siveke
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004705:Endocytosis / Q000235:genetics*; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008679:Metaplasia; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009997:Osmotic Pressure; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D011230:Precancerous Conditions; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000235:genetics / Q000378:metabolism*
chemical_list: D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Acinar epithelial explants; Acinar-to-ductal metaplasia (ADM); Fluid-phase endocytosis; Mice models; Neural-Wiskott-Aldrich syndrome protein (N-WASP); Oncogenic KRas; Pancreatic ductal adenocarcinoma (PDAC)