Uncovering the Mechanisms of Metastasis in Fallopian Tube-Originated Ovarian Cancer

揭示输卵管源性卵巢癌的转移机制

基本信息

批准号：
10649622
负责人：
Yang Yang-Hartwich
金额：
$ 42.21万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-17 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649622
关键词：
3-Dimensional Adhesions Animals Automobile Driving Bioinformatics Biological Biological Assay Cancer Patient Cancer cell line Carcinoma Carcinoma in Situ Cell Adhesion Cell physiology Cells Clinical Data Data Set Development Diagnosis Disease Disease-Free Survival Distal Epithelial Cells Family Family member Funding Genes Genetic Genetic Transcription Genetically Engineered Mouse Greater sac of peritoneum Human In Situ In Vitro Induced Mutation Interruption Knowledge Lesion Malignant Neoplasms Malignant neoplasm of ovary Mammalian Oviducts Mission Modeling Molecular Mus Mutation NF1 tumor suppressor Neoplasm Metastasis Organoids Outcome Ovarian Serous Adenocarcinoma Ovary Pathway Analysis Pathway interactions Patients Pattern Platinum Population Prognosis Proteins Recurrence Research Resistance Role Sampling Serous Source System TP53 gene Testing The Cancer Genome Atlas Tissue Stains Tumor Suppressor Genes Tumor stage Tumor-Associated Process United States National Institutes of Health Woman antitumor effect apoAI regulatory protein-1 brca gene cancer cell cancer initiation cancer stem cell cell motility cell transformation differential expression effective therapy genetic signature improved in vivo inhibitor insight intraperitoneal knock-down metastatic process migration mouse model neoplastic cell new therapeutic target novel ovarian neoplasm prevent promoter prostate cancer model protein expression single-cell RNA sequencing small molecule small molecule inhibitor therapeutic target transcription factor tumor tumor initiation tumor progression

项目摘要

The vast majority of ovarian cancer patients die from metastatic disease due to lack of effective treatments. To more successfully treat these women, we urgently need to better understand the molecular mechanisms of ovarian cancer metastasis. Up to 70% of ovarian cancers are high-grade serous carcinomas (HGSC). These cancers most commonly initiate from secretory epithelial cells in the fallopian tube (FT) and are highly metastatic. Genetic alterations, including BRCA and p53 mutations, facilitate the transformation of FT cells into serous tubal intraepithelial carcinomas as the precursor lesions of HGSCs. Cells then spread throughout the peritoneal cavity even before the clinically manifested “primary” ovarian tumors are detected, thus only 15% of patients are diagnosed with more- curable stage I disease. Very little is known about the molecular and cellular process driving the formation of disseminated intraperitoneal tumors. Our Ovgp1-iCreER BPRN mouse model recapitulates the development of precursor lesions from oviduct (equivalent of human FT) and forms metastatic HGSC, allowing us to explore the process of metastatic tumor development in HGSC. We carried out single-cell RNA-sequencing of oviducts and tumors from the BPRN mice and identified a population of tumor-initiating cells (TICs) with an increased ability to produce tumor organoids in vitro and form metastases in vivo. We validated their presence in human HGSC samples and found their gene signature to be enriched in 40% of HGSC patient samples in TCGA dataset and associated with poor prognosis. Using single-cell regulatory networks analysis, we determined that the nuclear receptor subfamily 2 group F member 2 (NR2F2) pathway was activated in these TICs. On the basis of our preliminary data and prior research, we hypothesize that NR2F2 pathway is critical for the FT-originated TICs to drive metastasis in HGSC. We propose three aims to test our hypothesis: 1) Define the molecular mechanism by which NR2F2 regulates migration and adhesion of ovarian cancer cells; 2) Characterize the expression and activation pattern of NR2F2 at different stages of tumor development in the BPRN mouse model. 3) Determine the biological and mechanistic effects of NR2F2 inhibition on metastasis of HGSC. The proposed study will provide novel insights into mechanisms of HGSC metastasis and inform the development of new strategies for inhibiting metastasis and prevent their recurrence in women with HGSC.

由于缺乏疗效，绝大多数卵巢癌患者死于转移性疾病为了更成功地治疗这些女性，我们迫切需要更好地了解这些治疗方法。卵巢癌转移的分子机制高达 70% 的卵巢癌是高级别癌症。浆液性癌（HGSC）这些癌症最常见于分泌性上皮细胞。输卵管 (FT) 具有高度转移性，包括 BRCA 和 p53 突变。促进FT细胞转化为浆液性输卵管上皮内癌作为前体 HGSC 的病变甚至在临床出现之前就扩散到整个腹膜腔。检测到明显的“原发性”卵巢肿瘤，因此只有 15% 的患者被诊断出患有更多- 对于可治愈的 I 期疾病的分子和细胞过程知之甚少。我们的 Ovgp1-iCreER BPRN 小鼠模型概括了播散性腹膜内肿瘤的形成。输卵管前体病变（相当于人类 FT）的发展并形成转移 HGSC，使我们能够探索 HGSC 中转移性肿瘤的发展过程。对 BPRN 小鼠的输卵管和肿瘤进行单细胞 RNA 测序，并鉴定了一组肿瘤起始细胞（TIC）在体外产生肿瘤类器官并形成的能力增强我们验证了它们在人类 HGSC 样本中的存在并发现了它们的基因。 TCGA 数据集中 40% 的 HGSC 患者样本中的签名得到丰富，并与不良相关通过单细胞调控网络分析，我们确定了核受体。根据我们的研究，亚家族 2 F 组成员 2 (NR2F2) 通路在这些 TIC 中被激活。根据初步数据和先前的研究，我们勇敢地认为 NR2F2 通路对于 FT 起源的 TIC 驱动 HGSC 转移我们提出三个目标来检验我们的假设：1）定义 NR2F2调节卵巢癌细胞迁移和粘附的分子机制2) 表征 NR2F2 在肿瘤发展不同阶段的表达和激活模式 BPRN 小鼠模型 3) 确定 NR2F2 抑制的生物学和机制效应。拟议的研究将为 HGSC 的机制提供新的见解。转移并为抑制转移和预防其转移的新策略的开发提供信息 HGSC 女性复发。