Microfluidic Models of Ovarian Cancer Preneoplastic Lesions

卵巢癌癌前病变的微流体模型

• 批准号: 10062680
• 负责人: Joanna E Burdette
• 金额: $ 7.19万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062680
• 关键词: 3-Dimensional; Anatomy; Biological; Cell model; Cessation of life; Collaborations; Collagen; Communication; Detection; Devices; Epithelial Cells; Fallopian Tube Neoplasms; Follicular Fluid; Grant; Homing; Hormones; Human; Lesion; Location; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Menarche; Menstrual cycle; Microfluidic Microchips; Microfluidics; Modeling; Names; National Institute of Environmental Health Sciences; Nature; Neoplasm Metastasis; Oral Contraceptives; Ovarian; Ovary; Ovulation; Paper; Physiological Processes; Pregnancy; Process; Proteins; Research Support; Risk; Risk Factors; Role; Sampling; Serous; Site; Source; System; Technology; Testing; Transgenic Mice; Tumor Cell Migration; cancer diagnosis; carcinogenesis; female reproductive system; human tissue; in vivo; invention; migration; mouse model; neoplastic cell; news; novel; preneoplastic cell; reproductive; response; small molecule; three dimensional cell culture; tumor; tumor initiation; versican

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.

卵巢癌是女性生殖系统最致命的癌症，超过 21,000 个新卵巢癌 美国每年有 14,000 人被诊断出癌症并死亡。月经周期，特别是总寿命 排卵次数是罹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、怀孕和初潮晚期。最常见和 卵巢癌的致命组织型，称为高级别浆液性癌（HGSC），可能起源于 是输卵管上皮细胞，而不是卵巢。卵巢肿瘤的频繁检测导致 “卵巢癌”这个名称表明卵巢为肿瘤提供了独特的解剖位置 迁移和扩张。由于大多数研究都支持输卵管是卵巢癌的根源， 了解排卵如何促进该部位肿瘤的发生变得至关重要。我们的团队开发了 最先进的微流体平台支持三维器官型培养，该平台支持 卵巢产生动态激素谱，与 28 天的人类生殖月经周期非常相似 和平台上的排卵。该设备是 C&E News 2017 年十大发明之一，我们的论文发表在 Nature Communications 是 2017 年 NIEHS 的顶级论文。该提案将建立在这一成功的基础上 合作扩展我们的技术和模型来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 来自以下来源的高级别浆液性癌症的肿瘤起始、迁移和肿瘤细胞扩增 输卵管。目标 1 将我们的卵巢 3D 培养和输卵管模型整合到一个新的模型中 PREDICT96 微流体装置可定义排卵的生理过程，特别是卵泡 液体，使用原代人类输卵管样本、肿瘤前细胞驱动输卵管肿瘤发生 Burdette 实验室开发的模型、肿瘤模型和转基因小鼠模型。在目标 2 中，我们将验证 3D 卵巢分泌的蛋白质 versican 的作用可增强输卵管归巢至卵巢 我们将使用 3D 离体微流体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逃逸的机制。 输卵管，我们假设这是由于球体形成和暴露的三​​- 排卵部位卵巢中的立体胶原蛋白。总的来说，这笔赠款将采用独特的设备，主要 人体组织和三维肿瘤前模型和肿瘤模型，以揭示新的生物靶点 努力减少卵巢中输卵管来源的高级别浆液性癌的肿瘤发生和扩散 微环境。