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

高级别浆液性卵巢癌中卵巢-输卵管轴的动态相互作用

• 批准号: 10667563
• 负责人: Joanna E Burdette
• 金额: $ 52.76万
• 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/10667563
• 关键词: 3-Dimensional; Activins; Adhesions; Advanced Glycosylation End Products; Aging; Anatomy; Biological; Cell model; Cells; Cessation of life; Clinical Management; Collaborations; Collagen; Communication; DNA Damage; Data; Detection; Development; Devices; Engineering; Epithelial Cells; Epithelium; Exposure to; Fallopian Tube Neoplasms; Follicular Fluid; Gel; Grant; Homing; Hormones; Human; Imaging technology; Lesion; Literature; Location; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Menarche; Menstrual cycle; Metastatic Malignant Neoplasm to the Ovary; Microfluidic Microchips; Microfluidics; Modeling; Monitor; Names; National Institute of Environmental Health Sciences; Nature; Neoplasm Metastasis; Operative Surgical Procedures; Oral Contraceptives; Organ; Ovarian; Ovarian Follicle; Ovary; Ovulation; Paper; Pathway interactions; Peritoneal; Peritoneal Fluid; Physiological; Physiological Processes; Pregnancy; Process; Protein Secretion; Proteins; Reactive Oxygen Species; Repression; Research Support; Risk; Risk Factors; Risk Reduction; Role; Sampling; Serous; Signal Transduction; Site; Source; Surface; System; Technology; Testing; Tissue Microarray; Tissues; Transforming Growth Factor beta; Transgenic Mice; Tubal Excisions; Tubal Ligation; Tumor Cell Migration; Tumor Expansion; Xenograft procedure; cancer diagnosis; cancer stem cell; carcinogenesis; design; female reproductive system; high risk; human tissue; in vivo; invention; migration; mortality; mouse model; neoplastic; neoplastic cell; news; novel; optical imaging; ovulation time; preneoplastic cell; prevent; reproductive; response; small molecule; stem cell biomarkers; three dimensional cell culture; tumor; tumor initiation; tumorigenesis; 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中最致命的癌症，有21,000多个新卵巢癌 在美国，癌症诊断和14,000例死亡。月经周期，特别是总寿命 排卵的数量是发展卵巢癌的关键危险因素。反映排卵的因素减少 卵巢癌的风险，例如口服避孕药，妊娠和初潮晚期。最常见的 卵巢癌的致命组织型，称为高级浆液癌（HGSC），可能起源于 输卵管上皮细胞，而不是卵巢。经常检测到卵巢中的肿瘤，这导致 在“卵巢癌”的名称中，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来源，所以 了解排卵如何有助于该站点的肿瘤创新，这变得至关重要。我们的团队发展了 在最先进的微流体平台上支持的三维有机文化，该平台支持 卵巢产生动态的骑马曲线，这些曲烯轮廓非常模仿28天的人类复制月经周期 和平台上的排卵。该设备是2017年C＆E新闻十大发明之一，我们的论文 自然通讯是2017年NIEHS的顶级论文。该提案将以这一成功为基础 合作以扩展我们的技术和模型，以研究卵巢在输卵管中的作用 癌变和转移。我们的假设是卵巢的微环境有助于 高级浆液癌的肿瘤起始，迁移和肿瘤细胞扩张 输卵管。 AIM 1将在一个新的 预测96微流体设备，以定义排卵的物理过程，特别是卵泡 流体，使用原发性人输卵管样品，产前塑性细胞驱动输卵管肿瘤倡议 模型，肿瘤模型和Burdette实验室中开发的转基因小鼠模型。在AIM 2中，我们将验证 分泌的蛋白质，versican的作用，从3D卵巢增强了输卵管归巢为卵巢 我们将测试小分子使用3D EX VIVO微流体来阻断卵巢定殖的能力 模型和体内。在AIM 3中，我们将研究导致肿瘤细胞逃脱的机制 输卵管，我们假设是由于球体的形成和暴露的三​​个 - 排卵部位的卵巢中的尺寸胶原蛋白。总体而言，该赠款将采用独特的设备，主要设备 人体组织以及三维前塑性和肿瘤模型，以揭示新的生物学靶标 努力减少输卵管衍生的高级浆液癌的肿瘤倡议和卵巢的传播 微环境。

项目成果

Increased Local Testosterone Levels Alter Human Fallopian Tube mRNA Profile and Signaling.

• DOI: 10.3390/cancers15072062
• 发表时间: 2023-03-30
• 期刊: Cancers
• 影响因子: 5.2

Silencing PTEN in the fallopian tube promotes enrichment of cancer stem cell-like function through loss of PAX2.

• DOI: 10.1038/s41419-021-03663-2
• 发表时间: 2021-04-07
• 期刊: Cell death & disease
• 影响因子: 9
• 作者: Russo A;Colina JA;Moy J;Baligod S;Czarnecki AA;Varughese P;Lantvit DD;Dean MJ;Burdette JE
• 通讯作者: Burdette JE

The Tumor Immune Profile of Murine Ovarian Cancer Models: An Essential Tool For Ovarian Cancer Immunotherapy Research.

• DOI: 10.1158/2767-9764.crc-22-0017
• 发表时间: 2022-06
• 期刊: Cancer research communications
• 作者: Rodriguez GM;Galpin KJC;Cook DP;Yakubovich E;Maranda V;Macdonald EA;Wilson-Sanchez J;Thomas AL;Burdette JE;Vanderhyden BC
• 通讯作者: Vanderhyden BC

Versican secreted by the ovary links ovulation and migration in fallopian tube derived serous cancer.

卵巢分泌的多功能蛋白聚糖与输卵管衍生浆液性癌的排卵和迁移有关。

• DOI: 10.1016/j.canlet.2022.215779
• 发表时间: 2022-09-01
• 期刊: CANCER LETTERS
• 影响因子: 9.7
• 作者: Russo, Angela;Yang, Zizhao;Heyrman, Georgette Moyle;Cain, Brian P.;Carrero, Alfredo Lopez;Isenberg, Brett C.;Dean, Matthew J.;Coppeta, Jonathan;Burdette, Joanna E.
• 通讯作者: Burdette, Joanna E.

Reply: Exposure of human fallopian tube epithelium to elevated testosterone results in alteration of cilia gene expression and beating.

答复：人类输卵管上皮暴露于升高的睾酮会导致纤毛基因表达和跳动的改变。

• DOI: 10.1093/humrep/deab022
• 发表时间: 2021
• 期刊: Human reproduction (Oxford, England)
• 作者: Jackson-Bey,Tia;Colina,José;Isenberg,BrettC;Coppeta,Jonathan;Urbanek,Margrit;Kim,JJulie;Woodruff,TeresaK;Burdette,JoannaE;Russo,Angela
• 通讯作者: Russo,Angela