Tumor stromal effects of DDR2 in metastasis regulation

项目摘要 现在认识到，肿瘤微环境有助于肿瘤细胞扩散和对肿瘤微环境的应答。 疗法肿瘤环境（或基质）由非肿瘤细胞、结构蛋白和嵌入的 生长因子和细胞因子，并且在乳腺肿瘤中，这些成分不同于它们的正常组织 在组成、架构和功能上的对应物。因此，对预防和 治疗乳腺癌转移的关键是了解肿瘤环境如何影响肿瘤细胞， 入侵/迁移能力。我们已经确定了一种新的胶原蛋白I刺激DDR2（RTK）信号通路 其在肿瘤细胞和肿瘤基质细胞中均具有活性，并且是乳腺癌转移的关键调节剂。 我们已经在遗传学上验证了DDR2作为一种新的和可行的治疗靶点，用于预防和治疗 转移性疾病由于其作用，肿瘤中DDR2活性的抑制应该影响两种肿瘤细胞， 肿瘤间质和肿瘤与其环境之间的沟通。 在肿瘤细胞中，我们已经证明DDR2通过胶原蛋白控制集体迁移/侵袭， 丰富的肿瘤ECM进入血管。在新的研究中，我们发现DDR2在肿瘤中的作用 间质控制ECM的产生、胶原纤维的组织和血管生成，但我们不知道其中的机制。 肿瘤间质内的细胞DDR2对这些作用以及如何重要。此外，我们发现， DDR2表现出不同的激酶依赖性和激酶非依赖性细胞效应，这可能会对细胞内的细胞凋亡构成挑战。 仅针对抑制激酶活性的疗法。由于DDR2在原发性肿瘤细胞内的作用， 由于间质对于转移是重要的，因此该提议集中于确定其在肿瘤间质中的功能。 有三个具体目标。在第一个目标中，我们将确定DDR2在哪些肿瘤基质细胞中起作用。 有助于改变肿瘤纤维化和胶原组织，以及如何。第二，我们将确定 DDR2的内皮细胞内在作用是否以及如何促进乳腺肿瘤血管生成。 最后，在第三个目标中，我们将确定转移的体内后果和作用机制 在乳腺肿瘤细胞和乳腺肿瘤CAF中的激酶非依赖性和激酶依赖性DDR2。

PROJECT SUMMARY It is now appreciated that the tumor microenvironment contributes to tumor cell spread and response to therapy. The tumor environment (or stroma) consists of non-tumor cells, structural proteins, and embedded growth factor and cytokines, and in breast tumors these components differ from their normal tissue counterparts in composition, architecture, and function. A major challenge then to the prevention and treatment of breast cancer metastasis is to understand how the tumor environment influences tumor cell invasive/migratory capacity. We have identified a novel collagen I stimulated DDR2 (a RTK) signaling pathway that is active in both tumor cells and tumor stromal cells and a critical regulator of breast cancer metastasis. We have genetically validated DDR2 as a novel and viable therapeutic target for prevention and treatment of metastatic disease. Because of its actions, inhibition of DDR2 activity in tumors should affect both tumor cells, tumor stroma and the communication between tumors and their environment. In tumor cells, we have shown that DDR2 controls collective migration/invasion through the collagen- rich tumor ECM to access blood vessels. In new work we have found that the action of DDR2 in the tumor stroma controls ECM production, collagen fiber organization, and angiogenesis, yet we do not know in which cells within the tumor stroma DDR2 is important for these effects and how. Furthermore, we have found that DDR2 exhibits distinct kinase-dependent and kinase-independent cellular effects that could pose challenges to therapies directed only at inhibiting kinase activity. Since the action of DDR2 within cells of the primary tumor stroma is important for metastasis, this proposal is focused on determining its function(s) in the tumor stroma. There are three specific aims. In the first aim we will determine in which tumor stroma cells the action of DDR2 contributes to changes to tumor fibrosis and collagen organization, and how. Second, we will determine whether the endothelial cell intrinsic action of DDR2 contribute to the breast tumor angiogenesis and how. Finally, in the third aim we will determine the in vivo consequences for metastasis and mechanism(s) of action of kinase-independent and kinase-dependent DDR2 in breast tumor cells and breast tumor CAFs.