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最致命的癌症，超过 21,000 个新卵巢癌 美国每年有 14,000 例癌症诊断和死亡。 排卵次数减少是罹患卵巢癌的关键危险因素。 卵巢癌的风险，如口服避孕药、怀孕和初潮晚期。 卵巢癌的致命组织型，称为高级别浆液性癌（HGSC），可能起源于 输卵管上皮细胞，而不是卵巢 卵巢中经常检测到肿瘤，这导致了。 “卵巢癌”这个名称表明卵巢为肿瘤提供了独特的解剖位置 由于大多数研究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。 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 该设备是 C&E 新闻 2017 年十大发明之一，也是我们的论文之一。 《自然通讯》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 我们的假设是卵巢的微环境有助于癌症发生和转移。 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 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 在目标 2 中，我们将验证 Burdette 实验室开发的模型、肿瘤模型和转基因小鼠模型。 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 在目标 3 中，我们将研究肿瘤细胞逃逸的机制。 我们勇敢的输卵管是由于球体的形成和暴露的三​​- 总体而言，这项资助将采用独特的设备，主要是在排卵部位的卵巢中产生三维胶原蛋白。 人体组织和三维肿瘤前模型和肿瘤模型，以揭示新的生物靶标 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。

项目成果

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

局部睾酮水平升高会改变人类输卵管 mRNA 谱和信号传导。

• 发表时间: 2023-03-30
• 影响因子: 5.2
• 作者: Russo, Angela;Cain, Brian P;Jackson;Lopez Carrero, Alfredo;Miglo, Jane;MacLaughlan, Shannon;Isenberg, Brett C;Coppeta, Jonathan;Burdette, Joanna E
• 通讯作者: Burdette, Joanna E

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

小鼠卵巢癌模型的肿瘤免疫特征：卵巢癌免疫治疗研究的重要工具。

• 发表时间: 2022-06
• 作者: Rodriguez, Galaxia M;Galpin, Kristianne J C;Cook, David P;Yakubovich, Edward;Maranda, Vincent;Macdonald, Elizabeth A;Wilson;Thomas, Anjali L;Burdette, Joanna E;Vanderhyden, Barbara C
• 通讯作者: Vanderhyden, Barbara C

Loss of PTEN in Fallopian Tube Epithelium Results in Multicellular Tumor Spheroid Formation and Metastasis to the Ovary.

输卵管上皮中 PTEN 的缺失导致多细胞肿瘤球体形成和卵巢转移。

• 发表时间: 2019-06-25
• 影响因子: 5.2
• 作者: Dean, Matthew;Jin, Vivian;Bergsten, Tova M;Austin, Julia R;Lantvit, Daniel D;Russo, Angela;Burdette, Joanna E
• 通讯作者: Burdette, Joanna E

Fallopian tube initiation of high grade serous ovarian cancer and ovarian metastasis: Mechanisms and therapeutic implications.

• DOI: 10.1016/j.canlet.2020.02.017
• 发表时间: 2020-02-14
• 期刊: Cancer letters
• 影响因子: 9.7
• 作者: Tova M Bergsten;J. Burdette;M. Dean
• 通讯作者: M. Dean

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。

• 发表时间: 2021
• 作者: Jackson;Colina, José;Isenberg, Brett C;Coppeta, Jonathan;Urbanek, Margrit;Kim, J Julie;Woodruff, Teresa K;Burdette, Joanna E;Russo, Angela
• 通讯作者: Russo, Angela