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死于转移性疾病，由于缺乏有效的治疗。 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）。这些癌症最常见地起始于上皮细胞中的分泌性上皮细胞， 输卵管（FT），并高度转移。遗传改变，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。然后细胞扩散到整个腹膜腔，甚至在临床应用之前。 表现为“原发性”卵巢肿瘤被检测到，因此只有15%的患者被诊断出患有更多- 可治愈的I期疾病关于驱动细胞分裂的分子和细胞过程知之甚少。 形成播散性腹膜内肿瘤。我们的Ovgp 1-iCreER BPRN小鼠模型概括了 从输卵管（相当于人FT）发展出前驱病变，并形成转移性 HGSC，使我们能够探索HGSC中转移性肿瘤发展的过程。我们进行 对BPRN小鼠的输卵管和肿瘤进行单细胞RNA测序， 肿瘤起始细胞（TIC）在体外产生肿瘤类器官的能力增加， 体内转移。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 在TCGA数据集中40%的HGSC患者样品中富集特征，并且与差 预后使用单细胞调控网络分析，我们确定核受体 亚家族2组F成员2（NR 2F 2）通路在这些TIC中被激活。根据我们的 初步数据和先前的研究，我们假设NR 2F 2途径是关键的FT起源的 TIC驱动HGSC中的转移。我们提出了三个目标来检验我们的假设：1）定义 NR 2F 2调节卵巢癌细胞迁移和粘附的分子机制; 2） 表征NR 2F 2在肿瘤发展的不同阶段的表达和激活模式， BPRN小鼠模型。3)确定NR 2F 2抑制对细胞凋亡的生物学和机制作用。 HGSC的转移。该研究将为HGSC的机制提供新的见解 转移，并为抑制转移和预防转移的新策略的发展提供信息。 HGSC女性的复发率。