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.
Highlights
Cholangiocarcinomas are highly lethal hepatobiliary cancers with features of cholangiocyte differentiation [1]
Yes-associated protein (YAP) Is Transcriptionally Active in Human CCA—We identified YAP protein expression (Fig. 1A) and YAP nuclear localization (Fig. 1B) in the KMCH and KMBC human CCA cell lines and minimal nuclear immunoreactivity in the nonmalignant Normal human cholangiocytes (NHC) cell line, despite abundant protein in the NHC cell lysates
Fibroblast Growth Factor Receptors Are Up-regulated by a YAP-dependent Mechanism—we assessed the expression of FGFR1– 4 in human CCA cell lines
Summary
FGFR4 overexpression has been associated with human CCA tumor progression and adverse survival [18]. These observations raise the specter that deregulated FGFR expression and signaling play a critical role in CCA biology. Inhibition of FGFR signaling with the pan-FGFR inhibitor BGJ398 results in YAP inactivation, CCA cell death, and tumor suppression in vivo. These observations help unravel an autocrine signaling cascade between two prominent oncogenic pathways and suggest that nuclear YAP expression may be a biomarker to employ in FGFR-directed therapy
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