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

• 批准号: 10419998
• 负责人: Yang Yang-Hartwich
• 金额: $ 44.08万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 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/10419998
• 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; Tube; Tumor Suppressor Genes; Tumor stage; Tumor-Associated Process; United States National Institutes of Health; Woman; Yang; 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

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.

绝大多数卵巢癌患者因缺乏有效治疗而死于转移性疾病。 治疗。为了更成功地治疗这些妇女，我们迫切需要更好地了解 卵巢癌转移的分子机制。高达70%的卵巢癌是高级别的 浆液性癌(HGSC)。这些癌症最常见的起源于卵巢癌的分泌上皮细胞。 输卵管(FT)和高度转移性。基因改变，包括BRCA和P53突变， 促进FT细胞向浆液性输卵管上皮内癌转化为前体 HGSCs的病变。然后细胞扩散到整个腹膜腔，甚至在临床上 表现为“原发”的卵巢肿瘤被检测出来，因此只有15%的患者被诊断出患有更多- 可治愈的I期疾病。对分子和细胞过程所知甚少 腹膜内播散性肿瘤的形成。我们的Ovgp1-iCreer BPRN小鼠模型概述 输卵管前驱病变的发生(相当于人输卵管)并形成转移 HGSC，使我们能够探索HGSC中转移肿瘤的发展过程。我们进行了一次 对BPRN小鼠的输卵管和肿瘤进行单细胞RNA测序，并鉴定出一个种群 肿瘤启动细胞(TICs)在体外产生和形成肿瘤有机化合物的能力增强 体内转移。我们证实了它们在人类HGSC样本中的存在，并发现了它们的基因 TCGA数据集中40%的HGSC患者样本中的签名要丰富，并与差相关 预后。利用单细胞调控网络分析，我们确定了核受体 亚家族2组F成员2(NR2F2)通路在这些抽动中被激活。基于我们的 初步数据和以前的研究，我们假设NR2F2通路对FT起源的 TICS可促进HGSC的转移。我们提出了三个目的来检验我们的假设：1)定义 NR2F2调控卵巢癌细胞迁移和黏附的分子机制 肿瘤发生发展不同阶段NR2F2的表达和激活模式 BPRN小鼠模型。3)确定NR2F2抑制作用的生物学和机制效应 HGSC的转移。这项拟议的研究将为HGSC的机制提供新的见解 转移和通知新的策略的发展，以抑制转移和预防其 患有HGSC的妇女的复发。