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

Lubeseder-Martellato, Clara; Alexandrow, Katharina; Hidalgo-Sastre, Ana; Heid, Irina; Boos, Sophie Luisa; Briel, Thomas; Schmid, Roland M.; Siveke, Jens T. LSF

Fluid-phase endocytosis is a homeostatic process with an unknown role in tumor initiation. The drivermutation 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 threedimensionalmouse and human acinar tissue cultures and genetically engineered mousemodels,we provide evidence that (i) KRasG12D leads 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 ADMformation 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 ADMemphasizing the in vivo relevance of our findings. Thiswork defines a new role of FPE as a tumor initiating mechanism.

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Lubeseder-Martellato, C., Alexandrow, K., Hidalgo-Sastre, A., Heid, I., Boos, S.L., Briel, T., Schmid, R.M., Siveke, J.T., 2017. Oncogenic KRas-induced Increase in Fluid-phase Endocytosis is Dependent on N-WASP and is Required for the Formation of Pancreatic Preneoplastic Lesions. https://doi.org/10.1016/j.ebiom.2016.12.013
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