Tumor stromal effects of DDR2 in metastasis regulation

项目总结 现在人们认识到，肿瘤微环境有助于肿瘤细胞的扩散和对 心理治疗。肿瘤环境(或间质)由非肿瘤细胞、结构蛋白和嵌入 生长因子和细胞因子，而在乳腺肿瘤中，这些成分与正常组织不同 在组成、架构和功能上具有对应性。这是预防和预防的一个重大挑战 乳腺癌转移的治疗就是了解肿瘤环境如何影响肿瘤细胞。 入侵/迁徙能力。我们发现了一种新的I型胶原刺激的DDR2(一种RTK)信号通路 它在肿瘤细胞和肿瘤间质细胞中都很活跃，是乳腺癌转移的关键调节因子。 我们已经从基因上证实了DDR2是一种新的和可行的预防和治疗癌症的治疗靶点 转移性疾病。由于它的作用，抑制肿瘤中的DDR2活性应该会影响两种肿瘤细胞， 肿瘤间质及肿瘤与周围环境的沟通。 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- 丰富的肿瘤细胞外基质可进入血管。在新的工作中，我们发现DDR2在肿瘤中的作用 基质控制细胞外基质的产生、胶原纤维的组织和血管生成，但我们还不知道是在哪一种。 肿瘤间质DDR2中的细胞对这些效应及其方式很重要。此外，我们发现， DDR2表现出不同的激酶依赖性和非依赖性的细胞效应，可能会对 仅针对抑制激酶活性的治疗。由于DDR2在原发肿瘤细胞内的作用 间质在肿瘤转移中起重要作用，本研究主要探讨其在肿瘤间质中的作用(S)。 有三个具体目标。在第一个目标中，我们将确定DDR2在哪些肿瘤间质细胞中的作用 有助于改变肿瘤纤维化和胶原蛋白的组织，以及如何。第二，我们将确定 DDR2的内皮细胞内在作用是否促进了乳腺肿瘤的血管生成，又是如何促进的。 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(S) 在乳腺肿瘤细胞和乳腺肿瘤CAF中的非依赖性和依赖性DDR2的研究。

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.