YAP induces high-grade serous carcinoma in fallopian tube secretory epithelial cells.

Ovarian cancer is the most lethal gynecological cancer. Globally, approximately 225,500 women are diagnosed with ovarian cancer annually, with an estimated 140,200 associated deaths worldwide1. The majority (~80%) of ovarian cancers are of epithelial origin. A key feature of high-grade serous carcinoma (HGSC), which constitutes 60–80% of ovarian epithelial carcinomas, is its aggressive nature and its unique genetic alterations2, 3. Patients with HGSC most frequently present at advanced clinical stages and have a very poor overall survival. The etiology of ovarian HGSC is unclear. Previous studies suggest that HGSC is derived from the neoplastic transformation of ovarian surface epithelial (OSE) cells in the cortical inclusion cysts of the ovary4, 5. However, the existence of a precursor lesion in the ovary that leads to HGSC has not been demonstrated conclusively6, 7. Studies using ovarian and Fallopian tube specimens from prophylactic salpingo-oophorectomy of BRCA1/2-mutation carriers suggest that most ovarian HGSC originate in the fimbrial end of the Fallopian tube8, 9. Recent studies indicate that ovarian HGSC, primary peritoneal carcinoma (PPC), and Fallopian tube cancer have similar pathogenesis and may originate from the same cell source, the Fallopian tube epithelial cells (FTSECs)10. Epidemiological studies also support the concept that ovarian, Fallopian tube, and primary peritoneal cancers have a common etiology11. Obviously, the conventional pathologic classification of many other pelvic serous cancers primarily as ovarian cancer contributes to underreporting the incidence of the Fallopian tube cancer because, in many cases, Fallopian tube cancers are also present on the surface of the ovary. The involvement of ovary in conventional ovarian HGSC is potentially a secondary event. Therefore, studies on the mechanisms underlying the initiation and progression of Fallopian tube HGSC represent a new and promising direction for the diagnosis and treatment of ovarian cancer. The etiology of the Fallopian tube cancer is also unknown. Recent studies suggest that disruption of the Hippo pathway is an important oncogenic event during tumorigenesis in many cancers12, 13. First discovered in Drosophila14,15, the Hippo pathway is a growth control pathway that is highly conserved throughout species16. Accumulating evidence indicates that the Hippo pathway has a fundamental role in organ size control, stem cell function, and tumor suppression. Hence, the Hippo pathway has attracted growing interest12, 13, 16. Activation of the Hippo pathway suppresses the activity of the transcriptional co-activator Yes-associated protein 1 (YAP1, commonly referred to as YAP) by phosphorylating YAP and subsequently retaining it in the cytoplasm. YAP has been identified as an ovarian cancer oncogene17,18. Our research also indicates that YAP contributes to ovarian cancer progression19,20. Although several very recent studies indicate the importance of FTSECs in the tumorigenesis of the Fallopian and ovarian HGSC11–14,21,22, the extent to which the Hippo pathway is involved in their initiation and progression has not been examined. In addition to limited information on the etiology, the molecular mechanism underlying the rapid progression of Fallopian tube and ovarian HGSCs is also unclear. Interestingly, previous studies have shown that cultured human FTSECs produce basic fibroblast growth factors (FGF2)23. FGF2, a growth regulatory peptide secreted from cells, is reported to be involved in a variety of biological processes including cell differentiation, cell growth, migration, angiogenesis, and tumor formation24. Most importantly, several Phase I and Phase II clinical trials for a pan FGF receptor inhibitor, BGJ39825, are currently underway to examine the role of this novel small molecule in the treatment of several solid tumors (http://clinicaltrials.gov/ct2/results?term=BGJ398&Search=Search). However, it is not known whether FGF2 secreted by FTSECs contribute to the tumorigenic process of Fallopian tube and ovarian HGSC. Whether the Hippo/YAP signaling pathway interacts with the FGF/FGFR signaling pathway to regulate the rapid progression of Fallopian tube and ovarian HGSC has not been investigated. In turn, the present study aims to determine if the Hippo/YAP signaling pathway is involved in initiation and progression of Fallopian tube-derived HGSC and the potential signaling mechanism(s) underlying the Hippo/YAP pathway regulation of HGSC initiation and progression.