Abstract MIP-058: YAP, VIA INTERACTIONS WITH THE FGF SIGNALING PATHWAY, REGULATES TUMORIGENESIS OF FALLOPIAN TUBE SECRETORY EPITHELIAL CELLS

Abstract

Abstract INTRODUCTION: Accumulating evidence indicates that ovarian high-grade serous carcinoma (HGSC) originates from Fallopian tube secretory epithelial cells (FTSECs). Our recent studies indicated that the Hippo/YAP signaling pathway contributes to transformation of ovarian surface epithelial cells. However, whether this pathway is also involved in the initiation and progression of FTSEC-derived ovarian HGSC has not been examined. AIMS: The present study aims to determine whether the Hippo/YAP signaling pathway plays a role in initiation and progression of Fallopian tube-derived HGSC and the potential mechanism(s) by which YAP regulates FTSEC tumorigenesis. RESULTS: Immunohistochemical analysis showed that YAP expression was very low in normal human fallopian tube and ovarian tissues. However, YAP immunosignals significantly increased in ovarian HGSCs, cancerous and inflammatory fallopian tube tissues. Data extracted from multidimensional human cancer genomics datasets revealed that the YAP and TEADs (the major target transcription factors of YAP) genes are frequently amplified and/or up-regulated, while the upstream tumor suppressor genes such as NF1 and LATS1, are frequently deleted and/or mutated in ovarian HGSC tissues. Overexpression of YAP in immortalized non-tumorigenic FTSECs promoted cell proliferation in both 2D and 3D culture systems, induced colony formation in soft agar, and drove tumorigenesis in athymic nude mice. Pathohistological and biochemical analyses clearly indicated that tumors derived from the FTSECs resembled ovarian HGSC. In addition, our mechanistic studies showed that activation of YAP in human FTSECs upregulated the expression of fibroblast growth factors (FGF1, FGF2) and their receptors (FGFR1, FGFR2, FGFR3 and FGFR4). Intriguingly, we found that the activated FGF signaling in turn suppressed the Hippo pathway and activated YAP protein. Consistent with this result, treatment of FTSECs with YAP antagonist (Verteporfin) and/or FGFR inhibitor (BGI398) not only blocked YAP-induced FTSECs transformation, but also suppressed tumor cell growth and induced tumor cell death in a human HGSC xenograft model. CONCLUSION: Our results demonstrate that the disruption of the Hippo/YAP signaling pathway contributes to the carcinogenesis of the fallopian tube secretory epithelial cells. The Hippo/YAP and FGF signaling pathways formed an autocrine/paracrine positive feedback loop to drive the progression of the FTSECs-derived HGSC. Evidence in this study strongly suggests that combined targeting of YAP and FGFRs represents a novel therapeutic strategy for ovarian HGSCs. Citation Format: Chunbo He, Guohua Hua, Xiangmin Lv, Zhengfeng Wang, Ronny I. Drapkin, John S. Davis, Cheng Wang. YAP, VIA INTERACTIONS WITH THE FGF SIGNALING PATHWAY, REGULATES TUMORIGENESIS OF FALLOPIAN TUBE SECRETORY EPITHELIAL CELLS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-058.