Intrahepatic cholangiocarcinoma (iCCA) is a lethal malignancy with limited therapeutic options. Previously, we demonstrated that Notch1 overexpression alone suffices to induce iCCA in the mouse, albeit after long latency. Here, we show that activation of the Yap protooncogene occurs during Notch1 driven iCCA progression. After co-expressing activated Notch1 (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 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. Altogether, our 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.Copyright © 2021. Published by Elsevier Inc.