Lubeseder-Martellato Clara, Alexandrow Katharina, Hidalgo-Sastre Ana, Heid Irina, Boos Sophie Luise, Briel Thomas, Schmid Roland M, Siveke Jens T
Clinic and Polyclinic for Internal Medicine II, Klinikum Rechts der Isar, Technical University of Munich, Germany.
Clinic and Polyclinic for Internal Medicine II, Klinikum Rechts der Isar, Technical University of Munich, Germany.
EBioMedicine. 2017 Feb;15:90-99. doi: 10.1016/j.ebiom.2016.12.013. Epub 2016 Dec 24.
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 KRas, which induces neoplastic transformation of acinar cells through acinar-to-ductal metaplasia (ADM). We have previously shown that KRas-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) KRas 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 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.
液相内吞作用是一种稳态过程，在肿瘤起始中的作用尚不清楚。胰腺导管腺癌（PDAC）中的驱动突变是组成型激活的KRas，它通过腺泡-导管化生（ADM）诱导腺泡细胞发生肿瘤转化。我们之前已经表明，KRas诱导的ADM通过一种尚未完全阐明的机制依赖于RAC1和表皮生长因子受体（EGFR）。利用三维小鼠和人类腺泡组织培养以及基因工程小鼠模型，我们提供了以下证据：（i）在腺泡化生过程中，KRas导致EGFR依赖的持续液相内吞作用（FPE）；（ii）质膜张力的变化增加FPE，并在体外独立于EGFR导致ADM；（iii）RAC1部分通过对FPE的肌动蛋白依赖性调节来调控ADM的形成。此外，胰腺特异性缺失F-肌动蛋白调节因子神经威斯科特-奥尔德里奇综合征蛋白（N-WASP）的小鼠FPE减少且ADM受损，这强调了我们研究结果在体内的相关性。这项工作确定了FPE作为一种肿瘤起始机制的新作用。
