# The Hippo Signaling Pathway in High Grade Serous Ovarian Carcinoma

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $323,858

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10468746
- **Project number:** 5R01CA197976-08
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Cheng Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $323,858
- **Award type:** 5
- **Project period:** 2016-05-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468746

## Citation

> US National Institutes of Health, RePORTER application 10468746, The Hippo Signaling Pathway in High Grade Serous Ovarian Carcinoma (5R01CA197976-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10468746. Licensed CC0.

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