The Hippo Signaling Pathway in High Grade Serous Ovarian Carcinoma

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PROJECT SUMMARY: Ovarian high-grade serous carcinoma (HGSC) is the most lethal gynecological cancer. The etiology of ovarian HGSC is largely unknown. Although recent studies (including ours) have identified the fallopian tube epithelial cell (FTECs) as a cell-of-origin of ovarian HGSC, the exact molecular mechanism(s) underlying initiation of HGSC from FTECs are still unclear. In the first funded period, our research results provide solid evidence that the disruption of the Hippo/YAP signaling pathway plays a critical role in the malignant transformation of immortalized FTECs and the development of HGSC from the immortalized fallopian tube and ovarian epithelial cells. Despite these findings, we found that it is challenging to induce HGSC from mouse oviduct epithelium by cell-specific expression of hyperactivated YAP1. Our mechanistic studies, unexpectedly, demonstrated that hyperactivation of YAP1 alone in the cultured primary FTEC induced cellular senescence. This surprising finding suggested that other factors likely prevent FTECs from YAP1-induced senescence during the malignant transformation process. The factor(s) that aid hyperactivated YAP1 in the induction of malignant transformation of FTECs are unknown. Our large-scale screening studies showed that infection of human papillomavirus (HPV) was sufficient to prevent cultured primary FTECs from hyperactivated YAP1-induced senescence. Consistently, our previous studies have shown that HPV16 E6 oncoprotein suppressed the Hippo pathway and stabilized YAP1 protein to promote the oncogenic action of YAP1. Intriguingly, our preliminary studies demonstrated that YAP1 facilitated HPV infection of cultured FTECs by increasing the expression of HPV receptor molecules and suppressing the innate immunity. Importantly HPV virions could reach FTECs under both physiological (sperm-transmission) and pathological (via retrograde menstruation) conditions. Based on the above evidence, we hypothesize that hyperactivated YAP1, via upregulating the putative HPV receptor molecules and suppressing the innate immunity, employs HPV to overcome oncogene-induced senescence and forms a YAP1-HPV oncogenic alliance to drive the initiation of HGSC in fallopian tube epithelium. In this project, we designed three specific aims to test our hypothesis. In specific aim 1, we will model the carcinogenic action of the YAP1-HPV alliance in fallopian tube epithelial cells using unique transgenic animal models and newly isolated mouse papillomavirus (MmuPV1). In specific aim 2, we designed experiments to reveal the molecular mechanism(s) by which the YAP1-HPV alliance drives fallopian tube carcinogenesis. In specific aim 3, we designed preclinical studies to evaluate the potential clinical applications of combined targeting HPV and YAP1 in the prevention and early detection of HGSC-derived from FTECs. Achieving the proposed studies could identify HPV as a neglected preventable risk factor for ovarian cancer. Identification of the functioning mechanism (s) of the YAP1-HPV oncogenic axis in the carcinogenesis of fallopian tube epithelium will provide new clues for developing strategies to improve the prevention and early detection of FTEC-derived HGSC.