Ovarian cancers are the most lethal gynaecological cancers in women in the USA. Despite the rapid progress made in ovarian cancer research in the past decades, the mortality of the epithelial ovarian cancer (EOC) is still very high. This may be attributed to the fact that the origin and pathogenesis of EOC are poorly understood. Recent studies identified the Fallopian tube secretory epithelial cell (FTSEC) as cell of origin for ovarin high-grade serious carcinoma (HGSC). However, the molecular mechanisms underlying the initiation of HGSC in the Fallopian tube, the colonization of HGSC cells in the ovary, and the final expansion of HGSC cells in the ovary are poorly understood. Studies in our laboratory find that YAP, the effector of the Hippo pathway, is able to initiate the transformation of FTSEC cells and promote the growth of FTSEC-derived tumors. We also find that YAP regulates genes and signalling pathways that are critical for tumour cell migration, invasion and angiogenesis, as well as growth factors involved in the ovarian tissues remodelling. Our preliminary studies further indicate that the Hippo/YAP signalling pathway interacts with the ErbB signalling pathway to promote the proliferation of ovarian HGSC cells. We hypothesize that the Hippo/YAP pathway plays critical roles on the initiation of HGSC in the fallopian tube, colonization of the FTSEC-derived HGSC cells in the ovary, and the final expansion and progression of the HGSC in the ovary after menopause. In this proposed project, we have designed in vivo and in vitro experiments to examine the function of the Hippo/YAP pathway on the initiation and progression of ovarian HGSC.
In specific aim 1, we will use transgenic mouse model to determine the role of the Hippo/YAP pathway in the initiation of HGSC in fallopian tube epithelial cells.
In specific aim 2, we will use genetically modified mouse model to investigate the biological events that lead to colonization of fallopian tube-derived tumour cells in the ovary.
In specific aim 3, we will determine how the Hippo/YAP pathway associated molecules and signalling pathways regulate the expansion of fallopian tube-derived tumour cells in the ovary. Successful completion of these proposed studies will answer the following questions: What is the molecular mechanism that initiates the transformation of FTSEC cells in the fallopian tube? How do the fallopian tube-derived tumour cells colonize in the ovary? What are the factors drive the initial expansion and subsequent progression of FTSEC-derived tumour 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 will open a new window for the prevention and therapy of epithelial ovarian cancer.
Ovarian cancer is the most lethal gynecological malignancy. The American Cancer Society estimates that in 2015 alone, 21,290 new cases of ovarian cancer will be diagnosed, and 14,180 women will die from ovarian cancer in the United States. Globally, ovarian cancer accounts for ~140,000 women's deaths per year. Knowing the origin of the ovarian cancer will facilitates the effective prevention of these deadly diseases. Uncovering the molecular mechanisms underlying the initiation and progression of the high grade serous ovarian carcinoma is expected to discover novel biomarkers for the early diagnosis and develop new drugs and therapeutic regime for a more effective treatment of ovarian cancer.
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