Investigating tumor-mesothelial cell interactions during ovarian cancer metastasis

项目总结 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局的驱动因素，但目前还没有有效的治疗方法 靶向转移。卵巢癌经常转移到腹膜腔，在那里它附着在 腹膜器官周围的间皮细胞，取代这一层，并侵入腹膜器官 下层基质。间皮细胞成为这一过程的积极参与者，沉积和重塑 肿瘤细胞可以附着的细胞外基质。因此，间皮细胞提供了一种有希望的治疗方法 目标。然而，它们允许转移的方式尚不完全清楚。 我们实验室的初步工作表明，间皮细胞表达的受体酪氨酸激酶 盘状结构域受体2(DDR2)促进肿瘤转移。将小鼠卵巢癌细胞注射入体内后 与DDR2全局敲除的小鼠相比，小鼠的肿瘤负担显著降低 到野生型小鼠。此外，体外初步数据表明，间皮细胞DDR2的抑制作用减弱 肿瘤细胞清除。此外，抑制间皮细胞DDR2可降低血管内皮细胞的蛋白表达。 间充质转录因子SNAI1与间充质相关蛋白的转录和分泌 基质金属蛋白酶-2，即使在没有胶原蛋白的情况下--DDR2的配体。本提案旨在1)确定 间皮细胞DDR2表达促进卵巢癌转移的机制和2)确定 间皮细胞中胶原依赖和非胶原依赖的DDR2信号转导通路的作用 转移的步骤。通过测试我拥有的体内间皮特异性DDR2基因敲除小鼠 产生(目标1)，并确定DDR2表达促进胶原非依赖性机制 转移(目标2)这一提议将检验DDR2作用于间皮细胞产生 环境允许卵巢癌在腹膜腔内转移。从长远来看，这项提议可以 有助于开发新的治疗方法，改善结果，延缓转移，延长生命 在患有卵巢癌的患者中。除了通过以下方式扩大我们对这些机制的理解之外 卵巢癌的哪些转移，这一建议将为培育发展新技能奠定基础 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.