A Hippo and Fibroblast Growth Factor Receptor Autocrine Pathway in Cholangiocarcinoma

• Published in: The Journal of biological chemistry 2016-04, Vol.291 (15), p.8031-8047
• Main Authors: Ilyas, Sumera I., Yamada, Daisaku, Hirsova, Petra, Bronk, Steven F., Werneburg, Nathan W., Krishnan, Anuradha, Salim, Warda, Zhang, Liang, Trushina, Eugenia, Truty, Mark J., Gores, Gregory J.
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - analysis; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; animal model; Animals; BGJ398; Bile Duct Neoplasms - genetics; Bile Duct Neoplasms - metabolism; Bile Duct Neoplasms - pathology; Bile Ducts - metabolism; Bile Ducts - pathology; cancer biology; Cell Line, Tumor; Cholangiocarcinoma - genetics; Cholangiocarcinoma - metabolism; Cholangiocarcinoma - pathology; fibroblast growth factor receptor (FGFR); Gene Expression Regulation, Neoplastic; Hippo pathway; Hippo Signaling Pathway; Humans; mcl-1; Mice; Mice, SCID; Molecular Bases of Disease; Phosphoproteins - analysis; Phosphoproteins - genetics; Phosphoproteins - metabolism; Protein Serine-Threonine Kinases - analysis; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Receptors, Fibroblast Growth Factor - analysis; Receptors, Fibroblast Growth Factor - genetics; Receptors, Fibroblast Growth Factor - metabolism; Signal Transduction; Transcription Factors; YAP-Signaling Proteins; Yes-associated protein (YAP)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.698472

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.