High grade serous ovarian carcinoma (HGSOC) is the most lethal gynecological cancer. The etiology of HGSOC is largely unknown. Although recent studies (including ours) have identified the Fallopian tube secretary epithelial cell as a cell-of-origin of HGSOC, the exact molecular mechanism(s) underlying initiation and progression of HGSOC from fallopian tube epithelial cells (FTECs) are still unclear. Our published data and preliminary studies provide evidence that the Hippo/YAP signaling pathway is involved in malignant transformation of FTECs. In the funded parent award, we designed three specific aims to examine our hypothesis that the Hippo/YAP pathway plays a critical role in transforming FTECs in the fallopian tube, facilitating the colonization of FTEC-derived tumor cells in the ovary, and promoting the dissemination of tumor cells in the pelvic cavity. While accomplishing the research goals of our parent grant, we unexpectedly found that hyperactivation of YAP1 in the cultured primary FTECs induced cellular senescence. This surprising finding suggested that other factors likely prevent FTECs from YAP1-induced senescence during malignant transformation process. Our large-scale screening studies showed that infection of human papillomavirus (HPV) was sufficient to prevent FTECs from YAP1- induced senescence. Our previous studies have also shown that HPV16 E6 oncoprotein suppressed the Hippo pathway, stabilized YAP1 protein and activated YAP1. Intriguingly, our preliminary data demonstrated that YAP1 facilitated HPV infection of cultured FTECs. Importantly, HPV virions could reach FTECs via retrograde menstruation or sperm-carrying. Based on provided evidence, we hypothesize that YAP1 and HPV form a feedforward loop to drive the malignant transformation of FTECs and promote progression of fallopian tube- derived high grade serous cancer. As an initial step to understand the YAP1-HPV feedforward loop in the development of HGSOC from fallopian tube, we designed two specific aims in this pilot project to unveil the molecular mechanism(s) that lead to the formation of YAP1-HPV feedforward loop.
In specific aim 1, we will examine the role of HPV infection in the activation of YAP1 in Fallopian tube epithelial cells using in vitro tools and transgenic mouse models.
In specific aim 2, we will examine the potential mechanism(s) by which YAP1 regulates HPV infection of FTECs using HPV Pseudovirions and our cellular and transgenic mouse models. Achieving the proposed studies could identify transient exposure of HPV as a previously neglected risk factors for HGSOC, and will potentially provide new target for the effective prevention and improved treatment of HGSOC. In addition, this study provides a perfect opportunity for my laboratory (focus on gynecological cancers) to establish new collaboration with Dr. Munger's laboratory (virology and HPV-associated cancer) and Dr. Howley's laboratory (focus on HPV biology and immunology), allowing us to combine our expertise to forge new multidisciplinary projects and approaches to explore the potential viral etiology of HGSOC.

Public Health Relevance

PUBLIC RELEVANCE/NARRITIVE Ovarian cancer is the most lethal gynecological cancer. HGSOC accounts for the vast majority of the ovarian cancer death. Identification of HPV as a critical risk factor for HGSOC provides us a new direction for effective prevention (vaccination) and early detection of HGSOC. Recognition of the role of YAP1-HPV feedforward loop in the carcinogenesis of fallopian tube epithelial cells provides a new target for developing strategies to improve the treatment of this deadly disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Cell Biology Study Section (TCB)
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Watson, Joanna M
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Massachusetts General Hospital
United States
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