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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. Therefore, we investigated the functional role of Notch signaling during tumorigenesis of the extrahepatic bile duct (EHBD) and GB. Activation of Notch signaling and oncogenic <jats:italic>Kras<\/jats:italic> resulted in the development of biliary intraepithelial neoplasia (BilINs) in the EHBD and GB, which were premalignant lesions that progressed to adenocarcinoma in mice. The expression of genes involved in the mTORC1 pathway was increased in biliary spheroids from <jats:italic>Hnf1b\u2010CreERT2<\/jats:italic>; <jats:italic>Kras<\/jats:italic><jats:sup><jats:italic>LSL\u2010G12D<\/jats:italic><\/jats:sup>; <jats:italic>Rosa26<\/jats:italic><jats:sup><jats:italic>LSL\u2010NotchIC<\/jats:italic><\/jats:sup> mice and inhibition of the mTORC1 pathway suppressed spheroid growth. Additionally, simultaneous activation of the PI3K\u2013AKT and Notch pathways in EHBD and GB induced biliary cancer development in mice. Consistent with this, we observed a significant correlation between activated NOTCH1 and phosphorylated Ribosomal Protein S6 (p\u2010S6) expression in human eCCA. Furthermore, inhibition of the mTORC1 pathway suppressed the growth of Notch\u2010activated human biliary cancer cells <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. Mechanistically, the Kras\/Notch\u2013Myc axis activated mTORC1 through TSC2 phosphorylation in mutant biliary spheroids. These data indicate that inhibition of the mTORC1 pathway could be an effective treatment strategy for Notch\u2010activated human eCCA. \u00a9 2023 The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6139","type":"journal-article","created":{"date-parts":[[2023,6,13]],"date-time":"2023-06-13T08:28:51Z","timestamp":1686644931000},"page":"478-492","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Simultaneous activation of Kras\u2013Akt and Notch pathways induces extrahepatic biliary cancer via the <scp>mTORC1<\/scp> pathway"],"prefix":"10.1002","volume":"260","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3836-1648","authenticated-orcid":false,"given":"Mio","family":"Namikawa","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology Kyoto University Graduate School of Medicine  Kyoto 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