Role of the microenvironment in ovarian cancer metastasis

项目摘要/摘要 所有卵巢癌患者中有一半在五年内死亡。这在很大程度上是因为他们的肿瘤在 化疗和腹膜腔内转移，最终阻断器官的功能，如 肠子。此外，没有FDA批准的药物阻止腹膜内转移的步骤。因此，新的 需要制定预防卵巢癌转移的策略。这项建议的重点是受体酪氨酸。 激酶盘状区受体2(DDR2)作为预防卵巢癌转移的候选靶点 以下是原因。首先，DDR2在74%的晚期高级别浆液性卵巢癌中过度表达 肿瘤和100%的转移。其次，肿瘤中DDR2水平较高的患者生存时间较短 而不是那些DDR2水平较低的人。第三，初步数据显示，在注射肿瘤细胞后，肿瘤形成 在同基因的DDR2基因敲除小鼠中，比那些小鼠更小，含有更少的胶原(DDR2的配体) 在DDR2野生型小鼠中。第四，有希望的小分子DDR2抑制剂已经被开发出来，不像所有的 其他受体酪氨酸激酶抑制剂结合并变构抑制DDR2的胞外区。这 该提案将检验中心假设，即间质细胞中的DDR2通过作用促进转移步骤 通过其配基胶原蛋白改变微环境。目标1将建立在强劲的初步数据显示的基础上 间质中的DDR2通过识别特定的间质细胞(成纤维细胞和间皮细胞)促进转移 细胞)和DDR2促进转移的步骤。这一目标将利用一大批人 原发大网膜基质细胞和卵巢肿瘤细胞。目的2将检验间皮细胞中DDR2的假设 细胞和/或成纤维细胞被I型胶原激活，导致基质金属蛋白酶2活性增加和 纤维粘连蛋白裂解。此外，这一目标将检验DDR2调节胶原蛋白数量和 在微环境中的组织，并将鉴定表达DDR2的成纤维细胞分泌的蛋白质 促进卵巢肿瘤细胞侵袭。AIM 3将评估一种新的DDR2抑制剂增强反应的能力 并找出与疗效相关的肿瘤微环境成分。除了……之外 在小鼠同基因和患者来源的卵巢癌异种移植模型中测试一种新的DDR2抑制剂 AIM将使用一种新的多参数荧光成像工具来确定肿瘤/基质细胞的表达模式 以及与小鼠和人类肿瘤治疗反应相关的细胞外基质信号。 这些目标的完成将揭示肿瘤微环境对 腹膜内转移，揭示新的潜在治疗靶点。

PROJECT SUMMARY / ABSTRACT Half of all ovarian cancer patients die within five years. This is largely because their tumors recur after chemotherapy and metastasize within the intraperitoneal cavity, eventually blocking function of organs such as the bowel. Additionally, no FDA-approved drugs block the steps of intraperitoneal metastasis. Thus, new strategies are needed to prevent ovarian cancer metastasis. This proposal focuses on the receptor tyrosine kinase Discoidin Domain Receptor 2 (DDR2) as a candidate target to prevent ovarian cancer metastasis for the following reasons. First, DDR2 is overexpressed in 74% of advanced-stage, high-grade serous human ovarian tumors and 100% of metastases. Second, patients whose tumors had higher levels of DDR2 had shorter survival than those with lower levels of DDR2. Third, preliminary data shows that, after tumor cell injection, tumors formed in syngeneic DDR2 knockout mice were smaller and contained less collagen (the ligand for DDR2) than those in DDR2 wild-type mice. Fourth, promising small molecule DDR2 inhibitors have been developed that, unlike all other receptor tyrosine kinase inhibitors, bind and allosterically inhibit the extracellular domain of DDR2. This proposal will test the central hypothesis that DDR2 in stromal cells promotes steps of metastasis by acting through its ligand collagen to alter the microenvironment. Aim 1 will build on strong preliminary data showing that DDR2 in the stroma promotes metastasis by identifying the particular stromal cells (fibroblasts and mesothelial cells) and steps in which DDR2 contributes to metastasis. This aim will make use of a large bank of human primary omental stromal cells and ovarian tumor cells. Aim 2 will test the hypothesis that DDR2 in the mesothelial cells, fibroblasts, or both is activated by collagen I, leading to increased matrix metalloprotease 2 activity and fibronectin cleavage. Additionally, this aim will test the hypothesis that DDR2 regulates collagen amount and organization in the microenvironment and will identify proteins secreted by DDR2-expressing fibroblasts that promote ovarian tumor cell invasion. Aim 3 will assess the ability of a novel DDR2 inhibitor to enhance response to chemotherapy, and identify tumor microenvironment components that correlate with response. In addition to testing a novel DDR2 inhibitor in mouse syngeneic and patient-derived xenograft models of ovarian cancer, this aim will use a novel, multi-parameter fluorescent imaging tool to define tumor/stromal cell expression patterns and extracellular matrix signatures that correlate with treatment response in mouse and human tumors. Completion of these aims will uncover novel mechanisms by which the tumor microenvironment contributes to intraperitoneal metastasis and reveal new potential targets for therapy.