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

 描述（由申请人提供）：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迅速的进展，但上皮性卵巢癌（EOC）的死亡率仍然很高。这可能 这可能是由于对EOC的起源和发病机制了解甚少。近年来的研究证实输卵管分泌上皮细胞（FTSEC）是卵巢高级别恶性肿瘤（HGSC）的起源细胞。然而，HGSC在输卵管中的起始、HGSC细胞在卵巢中的定殖以及HGSC细胞在卵巢中的最终扩增的分子机制知之甚少。本实验室的研究发现，Hippo通路的效应子雅普能够启动FTSEC细胞的转化并促进FTSEC衍生肿瘤的生长。我们还发现，雅普调节基因和信号通路，这些基因和信号通路对肿瘤细胞迁移、侵袭和血管生成至关重要 作为参与卵巢组织重塑的生长因子。我们的初步研究进一步表明，Hippo/雅普信号通路与ErbB信号通路相互作用，促进卵巢HGSC细胞的增殖。我们假设Hippo/雅普通路在输卵管中HGSC的起始、FTSEC衍生的HGSC细胞在卵巢中的定殖以及绝经后HGSC在卵巢中的最终扩增和进展中起关键作用。在这个项目中，我们设计了体内和体外实验来研究Hippo/雅普通路在卵巢HGSC的启动和进展中的功能。在具体目标1中，我们将使用转基因小鼠模型来确定Hippo/雅普途径在输卵管上皮细胞中HGSC起始中的作用。具体目标 2，我们将使用转基因小鼠模型来研究导致输卵管源性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Hippo/雅普途径相关分子和信号传导途径如何调节卵巢中输卵管源性肿瘤细胞的扩增。成功完成这些拟议的研究将回答以下问题：启动输卵管FTSEC细胞转化的分子机制是什么？输卵管源性肿瘤细胞如何在卵巢中定植？是什么因素驱动FTSEC衍生的肿瘤细胞在卵巢中的初始扩增和随后的进展？该项目的完成将为我们对卵巢HGSC的发生和发展提供新的见解，并将为上皮性卵巢癌的预防和治疗打开一个新的窗口。

 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.