Simultaneous activation of Kras-Akt and Notch pathways induces extrahepatic biliary cancer via mTORC1 pathway

Biliary tract cancer (BTC) has poor prognosis. The Notch receptor is aberrantly expressed in extrahepatic cholangiocarcinoma (eCCA). However, the role of Notch signaling in the initiation and progression of eCCA and gallbladder (GB) cancer remains unknown. We investigated the functional role of Notch signaling during tumorigenesis of the extrahepatic bile duct and GB. We demonstrated that simultaneous activation of the Kras–Akt and Notch pathways in EHBD and GB resulted in the formation of BilINs and biliary cancer in a mouse model. Mechanistically, the Kras/Notch–Myc axis activates mTORC1 through phosphorylation of TSC2 in biliary tumorigenesis. We used biliary spheroids developed from biliary tract of mice in which KRAS-AKT and Notch pathways were activated (HKN). We also used biliary spheroids developed from biliary tract of wild type mice (C) and mice in which either Kras or Notch pathway is activated (HK, HN) as control samples.