Investigating tumor-mesothelial cell interactions during ovarian cancer metastasis

研究卵巢癌转移过程中肿瘤-间皮细胞的相互作用

• 批准号: 10605017
• 负责人: Angela Schab
• 金额: $ 3.17万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2025-10-19
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605017
• 关键词: Abdomen; Adopted; Affect; Architecture; Automobile Driving; Binding; Cancer Biology; Cancer Etiology; Cell Communication; Cell-Matrix Junction; Cells; Cessation of life; Collagen; Data; Deposition; Development; Disease; E-Cadherin; Environment; Exposure to; Extracellular Matrix; Female; Fibroblasts; Fibronectins; Fostering; Foundations; Gelatinase A; Genetic Transcription; Goals; Greater sac of peritoneum; Human; Implant; In Vitro; Intercellular Junctions; Invaded; Knock-out; Knockout Mice; Life; Ligands; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mesenchymal; Mesothelial Cell; Mesothelial Neoplasms; Mesothelium; Metalloproteases; Modeling; Mus; Neoplasm Metastasis; Organ; Outcome; Participant; Patients; Penetration; Peritoneal Mesothelial Cell; Peritoneum; Process; Property; Proteins; Receptor Protein-Tyrosine Kinases; Research Personnel; Research Training; Role; Signal Transduction; Testing; Tumor Burden; Tumor Cell Invasion; Wild Type Mouse; Woman; Work; cancer cell; career; clinically relevant; discoidin domain receptor 2; effective therapy; experience; experimental study; improved outcome; in vivo; in vivo evaluation; intraperitoneal; knock-down; metastatic process; mutant; neoplastic cell; new therapeutic target; novel therapeutics; ovarian neoplasm; permissiveness; prevent; protein expression; receptor expression; skills; small hairpin RNA; targeted treatment; therapeutic target; transcription factor; translational approach; tumor microenvironment

PROJECT SUMMARY Ovarian cancer is the leading cause of gynecological cancer-related deaths. The propensity for metastasis is a driving factor for the poor outcomes associated with this disease, but there is yet to be an effective therapy targeting metastasis. Ovarian cancer frequently metastasizes to the peritoneal cavity, where it attaches to mesothelial cells surrounding the organs of the peritoneum, displaces this layer, and invades into the underlying stroma. Mesothelial cells become active participants in this process, depositing and remodeling extracellular matrix to which tumor cells can adhere. Mesothelial cells therefore offer a promising therapeutic target. However, the manner in which they become permissive to metastasis is not yet fully understood. Preliminary work from our lab suggests that mesothelial cell expression of the receptor tyrosine kinase Discoidin Domain Receptor 2 (DDR2) promotes metastasis. After injecting mouse ovarian cancer cells into mice, mice in which Ddr2 is globally knocked out demonstrate significantly decreased tumor burden compared to wild type mice. Further, in vitro preliminary data suggests that inhibition of mesothelial cell DDR2 decreases tumor cell clearance. Additionally, inhibition of mesothelial DDR2 decreases protein expression of the mesenchymal transcription factor SNAI1, and transcription and secretion of mesenchymal associated protein MMP-2, even in the absence of collagen - the ligand of DDR2. This proposal aims to 1) determine the mechanisms by which mesothelial DDR2 expression contributes to ovarian cancer metastasis and 2) define the effects of collagen-dependent vs. collagen-independent DDR2 signaling in mesothelial cells during the steps of metastasis. Through testing an in vivo mesothelial-specific Ddr2 knockout mouse that I have generated (Aim 1) and identifying collagen-independent mechanisms by which DDR2 expression contributes to metastasis (Aim 2) this proposal will test the hypothesis that DDR2 acting in mesothelial cells creates an environment permissive to ovarian cancer metastasis in the peritoneal cavity. In the long run, this proposal can contribute to the development of new therapeutics that improve outcomes, delay metastases, and prolong life in patients suffering from ovarian cancer. In addition to expanding our understanding of the mechanisms by which ovarian cancer metastasizes, this proposal will foster the development of new skills to lay the foundation for a lifelong career in the study of cancer biology.

项目摘要 卵巢癌是妇科癌症相关死亡的主要原因。转移的倾向是 与这种疾病相关的不良结果的驱动因素，但尚未有有效的疗法 靶向转移。卵巢癌经常向腹膜腔转移到 围绕腹膜器官的间皮细胞移位，并入侵 基础基质。间皮细胞成为此过程中的积极参与者，沉积和重塑 肿瘤细胞可以粘附到的细胞外基质。因此，间皮细胞提供有希望的治疗 目标。但是，他们允许转移的方式尚未完全理解。 我们实验室的初步工作表明受体酪氨酸激酶的间皮细胞表达 盘状结构域受体2（DDR2）促进转移。将小鼠卵巢癌细胞注入 小鼠，在全球击落DDR2的小鼠表明肿瘤负担显着减轻 到野生型小鼠。此外，体外初步数据表明，间皮细胞DDR2的抑制作用降低 肿瘤细胞清除。另外，抑制间皮DDR2降低了蛋白质的表达 间充质转录因子SNAI1，以及间充质相关蛋白的转录和分泌 MMP -2，即使在没有胶原蛋白的情况下 - DDR2的配体。该建议的目的是1）确定 间皮DDR2表达有助于卵巢癌转移的机制，2）定义 胶原蛋白依赖性与胶原蛋白与胶原蛋白与胶原蛋白非依赖性DDR2信号在间皮细胞中的影响 转移的步骤。通过测试我拥有的体内间皮特异性DDR2敲除鼠标 生成（AIM 1）并鉴定与胶原蛋白无关的机制，DDR2表达有助于 转移（AIM 2）该提案将检验以下假设，即DDR2作用在间皮细胞中会产生一个 环境允许腹膜腔中的卵巢癌转移。从长远来看，这个建议可以 有助于开发新的治疗剂，以改善结果，延迟转移和延长寿命 患有卵巢癌的患者。除了扩大我们对机制的理解 卵巢癌转移了哪些，该建议将促进发展基础的新技能 从事癌症生物学研究的终身职业。