Investigator, Assoc Prof (M) Vincent Center for Reproductive Biology, Mass General Research Institute

Associate Professor of Obstetrics, Gynecology and Reproductive Biology Obstetrics Gynecology & Repro. Bio. , Harvard Medical School

cervical cancer; fallopian tube neoplasms; follicle development; ftsec; hippo/yap signaling pathway; hpv; oncoproteins; ovarian cancer; ovarian high grade serious carcinoma; ovarian physiology

Defining the functional significance of the Hippo/YAP signaling pathway in the initiation and/or progression of the fallopian tube secretory epithelial cell (FTSEC)-derived ovarian high-grade serious carcinoma (HGSC)

Our goal is to explore roles of the Hippo/YAP signaling pathway in the initiation and progression of ovarian high-grade serious carcinoma (HGSC) with a FTSEC origin. These proposed studies are expected to answer the following questions:

• What is the molecular mechanism that initiates the transformation of FTSEC in the fallopian tube?
• How do the fallopian tube-derived tumor cells colonize in the ovary?
• What are the factors that drive the initial expansion of FTSEC-derived tumor cells in the ovary?

Achievement of this proposed project will provide new insight into our understanding on the development and progression of ovarian HGSC and could open a new window for the prevention and therapy of ovarian cancer.

With the help from many collaborators, we have established several important transgenic mouse strains to develop the fallopian tube-specific and ovary-specific MST1/2 knockout and YAP knockin mouse models. These are powerful tools for studying the role of the Hippo pathway in ovarian HGSC.

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Delineating the paracrine and autocrine regulation of ovarian function

The basic functional unit of the ovary is the follicle. Narrowly regulated cell-cell communication plays critical role in the follicle cell proliferation, differentiation, steroidogenesis, oocyte maturation and ovulation.

Our previous findings suggested ovarian follicle development is not only controlled by the hypothalamus-pituitary-gonad axis, but also tightly regulated by local growth factors, hormones, and cell adhesion molecules.

In particular, our previous study unveiled the role of GPR30 (now call GPER1), the membrane G protein-coupled estrogen receptor, in mediating the estrogen action during ovarian cell-cell communication and follicle development. These findings bolstered our understanding on the mechanisms underlying the endocrine, paracrine and autocrine regulation of ovarian physiology.

It is our hope that providing a better understanding of the key signaling pathways in the ovary will aid in the pursuit of overcoming infertility which impacts a significant number of women.

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Demonstrating how the Hippo-Yap signaling pathway, interacts with high-risk HPV oncoproteins to regulate cervical epithelial cell transformation and cervical cancer cell proliferation.

Cervical cancer is the fourth leading cause of cancer death in women. Although high risk human HPVs are thought to be the cause of cervical cancer, convincing evidence indicates that HPV alone is insufficient to induce cervical carcinogenesis.

The molecular mechanisms underlying cervical tumorigenesis are unclear. Our recent preliminary studies showed that YAP, the major effector of the Hippo tumor suppressive pathway, interacts with high-risk HPV oncoproteins to regulate cervical epithelial cell transformation and cervical cancer cell proliferation.

Based on these novel findings, we hypothesize that the Hippo pathway interacts with the high-risk HPV to drive the initiation and progression of cervical cancer.

Our proposed studies are designed to uncover the pathological role of the interaction between the high-risk HPV oncoproteins and the Hippo/YAP pathway and to unveil the molecular mechanisms underlying the observed crosstalk.