title: Notch3 drives development and progression of cholangiocarcinoma.
abstract: The prognosis of cholangiocarcinoma (CC) is dismal. Notch has been identified as a potential driver; forced exogenous overexpression of Notch1 in hepatocytes results in the formation of biliary tumors. In human disease, however, it is unknown which components of the endogenously signaling pathway are required for tumorigenesis, how these orchestrate cancer, and how they can be targeted for therapy. Here we characterize Notch in human-resected CC, a toxin-driven model in rats, and a transgenic mouse model in which p53 deletion is targeted to biliary epithelia and CC induced using the hepatocarcinogen thioacetamide. We find that across species, the atypical receptor NOTCH3 is differentially overexpressed; it is progressively up-regulated with disease development and promotes tumor cell survival via activation of PI3k-Akt. We use genetic KO studies to show that tumor growth significantly attenuates after Notch3 deletion and demonstrate signaling occurs via a noncanonical pathway independent of the mediator of classical Notch, Recombinant Signal Binding Protein for Immunoglobulin Kappa J Region (RBPJ). These data present an opportunity in this aggressive cancer to selectively target Notch, bypassing toxicities known to be RBPJ dependent.
authors: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, United Kingdom; Department of Surgery, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, United Kingdom; rachel.guest@ed.ac.uk stuart.forbes@ed.ac.uk.
authors: Rachel V
authors: RV
authors: Guest
authors: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, United Kingdom; Medical Research Council Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
authors: Luke
authors: 0000-0002-7954-6705
authors: L
authors: Boulter
authors: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, United Kingdom.
authors: Benjamin J
authors: BJ
authors: Dwyer
authors: Medical Research Council Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom; Medical Research Council Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors: Timothy J
authors: TJ
authors: Kendall
authors: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, United Kingdom.
authors: Tak-Yung
authors: TY
authors: Man
authors: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, United Kingdom.
authors: Sarah E
authors: SE
authors: Minnis-Lyons
authors: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, United Kingdom.
authors: Wei-Yu
authors: WY
authors: Lu
authors: Department of Surgery, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, United Kingdom; Medical Research Council Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors: Andrew J
authors: AJ
authors: Robson
authors: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, United Kingdom.
authors: Sofia Ferreira
authors: SF
authors: Gonzalez
authors: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, United Kingdom.
authors: Alexander
authors: A
authors: Raven
authors: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, United Kingdom.
authors: Davina
authors: D
authors: Wojtacha
authors: Cancer Research UK Beatson Institute, Glasgow G61 1BD, United Kingdom.
authors: Jennifer P
authors: JP
authors: Morton
authors: Translational Cell & Tissue Research Unit, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
authors: Mina
authors: M
authors: Komuta
authors: Translational Cell & Tissue Research Unit, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
authors: Tania
authors: T
authors: Roskams
authors: Department of Surgery, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, United Kingdom; Medical Research Council Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors: Stephen J
authors: SJ
authors: Wigmore
authors: Cancer Research UK Beatson Institute, Glasgow G61 1BD, United Kingdom.
authors: Owen J
authors: OJ
authors: Sansom
authors: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, United Kingdom; The Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, United Kingdom rachel.guest@ed.ac.uk stuart.forbes@ed.ac.uk.
authors: Stuart J
authors: SJ
authors: Forbes
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007133:Immunoglobulin Joining Region / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011379:Prognosis; D051381:Rats; D000071656:Receptor, Notch3 / Q000235:genetics*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D007133:Immunoglobulin Joining Region; C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases
keywords: Notch; bile duct; cancer; cholangiocarcinoma; noncanonical