title: A Hippo and Fibroblast Growth Factor Receptor Autocrine Pathway in Cholangiocarcinoma.
abstract: Herein, we have identified cross-talk between the Hippo and fibroblast growth factor receptor (FGFR) oncogenic signaling pathways in cholangiocarcinoma (CCA). Yes-associated protein (YAP) nuclear localization and up-regulation of canonical target genes was observed in CCA cell lines and a patient-derived xenograft (PDX). Expression of FGFR1, -2, and -4 was identified in human CCA cell lines, driven, in part, by YAP coactivation of TBX5. In turn, FGFR signaling in a cell line with minimal basal YAP expression induced its cellular protein expression and nuclear localization. Treatment of YAP-positive CCA cell lines with BGJ398, a pan-FGFR inhibitor, resulted in a decrease in YAP activation. FGFR activation of YAP appears to be driven largely by FGF5 activation of FGFR2, as siRNA silencing of this ligand or receptor, respectively, inhibited YAP nuclear localization. BGJ398 treatment of YAP-expressing cells induced cell death due to Mcl-1 depletion. In a YAP-associated mouse model of CCA, expression of FGFR 1, 2, and 4 was also significantly increased. Accordingly, BGJ398 treatment was tumor-suppressive in this model and in a YAP-positive PDX model. These preclinical data suggest not only that the YAP and Hippo signaling pathways culminate in an Mcl-1-regulated tumor survival pathway but also that nuclear YAP expression may be a biomarker to employ in FGFR-directed therapy.
authors.affiliation: From the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Sumera I
authors.initials: SI
authors.lastname: Ilyas
authors.affiliation: From the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Daisaku
authors.initials: D
authors.lastname: Yamada
authors.affiliation: From the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Petra
authors.initials: P
authors.lastname: Hirsova
authors.affiliation: From the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Bronk
authors.affiliation: From the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Werneburg
authors.affiliation: From the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Krishnan
authors.affiliation: From the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Warda
authors.initials: W
authors.lastname: Salim
authors.affiliation: the Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: the Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905, the Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, and.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Trushina
authors.affiliation: the Department of Surgery, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Truty
authors.affiliation: From the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905, gores.gregory@mayo.edu.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gores
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001652:Bile Ducts / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D000090683:Hippo Signaling Pathway; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D010750:Phosphoproteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D017468:Receptors, Fibroblast Growth Factor / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D017468:Receptors, Fibroblast Growth Factor; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: BGJ398; Hippo pathway; Yes-associated protein (YAP); animal model; cancer biology; fibroblast growth factor receptor (FGFR); mcl-1
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