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The Hippo/YAP Signaling Pathway in Ovarian High Grade Serous Carcinoma

卵巢高级别浆液性癌中的 Hippo/YAP 信号通路

基本信息

批准号：
9107108
负责人：
Cheng Wang
金额：
$ 34.43万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9107108
关键词：
Accounting Achievement American Cancer Society Automobile Driving Biological Cancer Etiology Carcinoma Cell Proliferation Cell model Cells Cessation of life Data Development Diagnosis Disease Early Diagnosis Epithelial Cells Epithelial ovarian cancer Etiology Event Fallopian Tube Carcinoma Figs - dietary Geography Growth In Vitro Knock-in Mouse Knockout Mice Laboratory Finding Lead Malignant - descriptor Malignant Epithelial Cell Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Mammalian Oviducts Menopause Molecular Organ Organ Size Ovarian Ovarian Serous Adenocarcinoma Ovarian Tissue Ovary Ovulation Pathogenesis Pathway interactions Patients Play Prevention Prevention therapy Reporting Role Serous Signal Pathway Signal Transduction Signaling Protein System Therapeutic Tissues Transgenic Mice Tumor Cell Migration Tumor-Derived United States Woman Xenograft Model angiogenesis anticancer research base cancer cell design effective therapy in vivo insight mortality mouse model neoplastic cell novel novel marker novel therapeutics public health relevance research study three dimensional cell culture tumor progression

项目摘要

DESCRIPTION (provided by applicant): 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.