Investigating tumor-mesothelial cell interactions during ovarian cancer metastasis

项目摘要 卵巢癌是妇科癌症相关死亡的主要原因。转移的倾向是一种 与这种疾病相关的不良结局的驱动因素，但尚未有有效的治疗方法 靶向转移。卵巢癌经常转移到腹膜腔，在那里它附着在 间皮细胞围绕腹膜的器官，取代这一层，并侵入 底层基质间皮细胞成为这一过程的积极参与者， 肿瘤细胞可以粘附的细胞外基质。因此，间皮细胞提供了一种有前途的治疗方法， 目标然而，它们变得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，间皮细胞受体酪氨酸激酶的表达 盘状结构域受体2（DDR2）促进转移。在将小鼠卵巢癌细胞注射到 在小鼠中，Ddr2被整体敲除的小鼠显示出显著降低的肿瘤负荷， 野生型小鼠。此外，体外初步数据表明，对间皮细胞DDR2的抑制降低， 肿瘤细胞清除率此外，间皮细胞DDR2的抑制降低了间皮细胞的蛋白质表达。 间充质转录因子SNAI1和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。本建议旨在：（1）确定 间皮细胞DDR2表达有助于卵巢癌转移的机制和2）定义 胶原依赖性与胶原非依赖性DDR2信号在间皮细胞中的作用 转移的步骤。通过测试体内间皮特异性Ddr2基因敲除小鼠， 产生（目的1），并确定胶原蛋白的非依赖性机制，其中DDR2表达有助于 转移（目的2）这一提议将检验DDR2在间皮细胞中起作用的假设， 卵巢癌转移的环境。从长远来看，这一建议可以 有助于开发新的治疗方法，改善结果，延迟转移，延长生命 卵巢癌患者的治疗除了通过以下方式扩展我们对机制的理解之外， 其中卵巢癌转移，这一建议将促进新技能的发展奠定基础 终身从事癌症生物学研究。

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.