relation: https://epub.uni-regensburg.de/56657/ title: YAP Accelerates Notch-Driven Cholangiocarcinogenesis via mTORC1 in Mice creator: Lu, Xinjun creator: Peng, Baogang creator: Chen, Ge creator: Pes, Mario G. creator: Ribback, Silvia creator: Ament, Cindy creator: Xu, Hongwei creator: Pal, Rajesh creator: Rodrigues, Pedro M. creator: Banales, Jesus M. creator: Evert, Matthias creator: Calvisi, Diego F. creator: Chen, Xin creator: Fan, Biao creator: Wang, Jingxiao subject: 610 Medizin subject: ddc:610 description: Intrahepatic cholangiocarcinoma (iCCA) is a lethal malignant neoplasm with limited therapeutic options. Previous studies have found that Notch1 overexpression alone suffices to induce iCCA in the mouse, albeit after long latency. The current study found that activation of the Yes-associated protein (Yap) proto-oncogene occurs during Notch1-driven iCCA progression. After co-expressing activated Notch1 intracellular domain (Nicd) and Yap (YapS127A) in the mouse liver, rapid iCCA formation and progression occurred in Nicd/Yap mice. Mechanistically, an increased expression of amino acid transporters and activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway was detected in Nicd/Yap mouse liver tumors. Significantly, the genetic deletion of Raptor, the major mTORC1 component, completely suppressed iCCA development in Nicd/Yap mice. Elevated expression of Notch1, YAP, amino acid transporters, and members of the mTORC1 pathway was also detected ubiquitously in a collection of human iCCA specimens. Their levels were associated with a poor patient outcome. This study demonstrates that Notch and YAP concomitant activation is frequent in human cholangiocarcinogenesis. Notch and YAP synergize to promote iCCA formation by activating the mTORC1 pathway. (Am J Pathol 2021, 191: 1651e1667; https://doi.org/10.1016/j.ajpath.2021.05.017) publisher: Elsevier date: 2021 type: info:eu-repo/semantics/article type: Artikel type: doc-type:article type: NonPeerReviewed identifier: Lu, Xinjun, Peng, Baogang, Chen, Ge, Pes, Mario G. , Ribback, Silvia, Ament, Cindy , Xu, Hongwei, Pal, Rajesh , Rodrigues, Pedro M. , Banales, Jesus M., Evert, Matthias, Calvisi, Diego F., Chen, Xin, Fan, Biao und Wang, Jingxiao (2021) YAP Accelerates Notch-Driven Cholangiocarcinogenesis via mTORC1 in Mice. The American Journal of Pathology 191 (9), S. 1651-1667. relation: http://doi.org/10.1016/j.ajpath.2021.05.017 relation: 10.1016/j.ajpath.2021.05.017