Dynamic Interactions of the Ovarian-Fallopian Axis in High Grade Serous Ovarian Cancer

卵巢癌是女性生殖系统最致命的癌症，每年有超过21，000例新的卵巢癌。 癌症诊断和14，000人死亡。月经周期，特别是整个生命周期 排卵次数是患卵巢癌的关键危险因素。抑制排卵的因素减少 卵巢癌的风险，如口服避孕药，怀孕和月经初潮后期。最常见和 一种致命的卵巢癌组织类型，称为高级别浆液性癌（HGSC），可能起源于卵巢癌。 输卵管上皮细胞而不是卵巢。卵巢肿瘤的频繁检测， 卵巢癌的名称表明卵巢为肿瘤提供了独特的解剖位置， 移民和扩张。由于大多数研究支持输卵管是卵巢癌的来源， 了解排卵如何促进该部位的肿瘤发生变得至关重要。我们的团队开发 三维器官型培养物支持在最先进的微流体平台中， 卵巢产生动态的激素分布，密切模仿28天的人类生殖月经周期 和排卵期该设备是2017年C&E新闻十大发明之一，我们的论文在 Nature Communications是2017年NIEHS的顶级论文。该提案将建立在这一成功 合作扩大我们的技术和模型，以研究卵巢在输卵管中的作用 致癌和转移。我们的假设是卵巢的微环境有助于 肿瘤的发生、迁移和肿瘤细胞的扩增， 输卵管目的1将我们的卵巢3D培养和输卵管模型整合到一个新的 PREDICT 96微流控装置来定义排卵的生理过程，特别是卵泡 使用原代人输卵管样品，癌前细胞， 模型、肿瘤模型和Burdette实验室开发的转基因小鼠模型。在目标2中，我们将验证 从3D卵巢分泌的蛋白质多功能蛋白聚糖的作用，其增强输卵管归巢到卵巢 我们将使用3D离体微流控技术测试小分子阻断卵巢定植的能力， 模型和体内。在目标3中，我们将研究肿瘤细胞从肿瘤细胞中逃逸的机制。 输卵管，我们假设这是由于球体的形成和暴露的三个殖民- 排卵部位卵巢中的三维胶原蛋白。总的来说，这笔赠款将采用独特的设备，主要 人体组织和三维癌前病变和肿瘤模型，以揭示新的生物靶点， 努力减少输卵管源性卵巢高级别浆液性癌的肿瘤发生和扩散 微环境

Ovarian cancer is the most lethal cancer of the female reproductive system, with over 21,000 new ovarian cancer diagnoses and 14,000 deaths annually in the US. The menstrual cycle, specifically the total lifetime number of ovulations, is a key risk factor for developing ovarian cancer. Factors that repress ovulation reduce the risk of ovarian cancer, such as oral contraceptives, pregnancy, and late menarche. The most common and deadly histotype of ovarian cancer, termed high grade serous cancer (HGSC), likely originates from the fallopian tube epithelial cells, and not the ovary. The frequent detection of tumors in the ovary, which resulted in the name “ovarian cancer”, suggests that the ovary provides a unique anatomical location for tumor migration and expansion. Since most research supports that the fallopian tube is the source of ovarian cancer, it becomes critical to understand how ovulation contributes to tumor initiation in this site. Our team developed three-dimensional organotypic cultures supported in a state-of-the-art microfluidic platform that supports the ovary to produce dynamic hormone profiles that closely mimic the 28-day human reproductive menstrual cycle and ovulation on platform. The device was one of the C&E News Top 10 Inventions of 2017 and our paper in Nature Communications was the top NIEHS paper of 2017. The proposal will build on this successful collaboration to expand our technology and models to studying the role of the ovary in fallopian tube carcinogenesis and metastasis. Our hypothesis is that the microenvironment of the ovary contributes to tumor initiation, migration, and tumor cell expansion of high grade serous cancers derived from fallopian tube. Aim 1 will integrate our 3D culture of the ovary and models of the fallopian tube in a new PREDICT96 microfluidic device to define the how the physiological process of ovulation, specifically follicular fluid, drives fallopian tube tumor initiation using primary human fallopian tube samples, preneoplastic cell models, tumor models, and a transgenic mouse model developed in the Burdette lab. In Aim 2, we will validate the role of the secreted protein, versican, from the 3D ovary that enhances fallopian tube homing to the ovary and we will test small molecules for their ability to block ovarian colonization using 3D ex vivo microfluidic models and in vivo. In Aim 3, we will investigate the mechanisms responsible for tumor cell escape from the fallopian tube, which we hypothesize is due to spheroid formation and the colonization of exposed three- dimensional collagen in the ovary at sites of ovulation. Overall, this grant will employ unique devices, primary human tissues, and three dimensional preneoplastic and tumor models to unveil new biological targets in an effort to reduce tumor initiation and spread of fallopian derived high grade serous cancer in the ovarian microenvironment.