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

• 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
• 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

 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.

 描述(申请人提供)：卵巢癌是美国女性中最致命的妇科癌症。尽管在过去的几十年里，卵巢癌的研究取得了快速的进展，但上皮性卵巢癌的死亡率仍然很高。今年5月 其原因是对卵巢癌的起源和发病机制知之甚少。最近的研究证实输卵管分泌上皮细胞(FTSEC)是卵巢高级别严重癌(HGSC)的起源细胞。然而，HGSC在输卵管中的起始、HGSC在卵巢中的定植以及HGSC在卵巢中的最终扩张的分子机制尚不清楚。我们实验室的研究发现，河马途径的效应者YAP能够启动FTSEC细胞的转化，并促进FTSEC来源的肿瘤的生长。我们还发现，yap还调节对肿瘤细胞迁移、侵袭和血管生成至关重要的基因和信号通路。 作为生长因子参与卵巢组织的重塑。我们的初步研究进一步表明，Hippo/YAP信号通路与ErbB信号通路相互作用，促进卵巢HGSC细胞的增殖。我们推测，HIPPO/YAP通路在HGSC在输卵管中的起始、FTSEC来源的HGSC在卵巢中的定植以及绝经后HGSC在卵巢中的最终扩张和进展中起关键作用。在这个拟议的项目中，我们设计了体内和体外实验来研究HIPPO/YAP通路在卵巢HGSC发生和发展中的作用。在具体目标1中，我们将使用转基因小鼠模型来确定Hippo/YAP通路在输卵管上皮细胞HGSC启动中的作用。以特定的目标 2、我们将使用转基因小鼠模型来研究导致输卵管肿瘤细胞在卵巢中定植的生物学事件。在具体目标3中，我们将确定河马/YAP通路相关分子和信号通路如何调节输卵管肿瘤细胞在卵巢中的扩张。这些拟议研究的成功完成将回答以下问题：启动输卵管FTSEC细胞转化的分子机制是什么？输卵管来源的肿瘤细胞如何在卵巢中定植？是什么因素推动了FTSEC衍生的卵巢肿瘤细胞最初的扩张和随后的进展？该项目的完成将为我们对卵巢HGSC的发展和进展提供新的认识，并将为卵巢上皮性癌的预防和治疗打开新的窗口。