Cellular Interactions with the Extracellular Matrix of the Tumor Microenvironment

肿瘤细胞和基质细胞与细胞外基质（ECM）的相互作用是肿瘤细胞增殖的重要组成部分。 微环境对肿瘤进展的影响。整合素是最重要的细胞 ECM的表面受体，并且它们经常与肿瘤进展和转移有关。 我们提出了三个项目，都是为了更深入地了解肿瘤和 基质细胞与肿瘤微环境的关系。其中一个项目深入分析了 我们最近发现的特异性肿瘤-微环境相互作用（GPR 56、TG 2及其 潜在的相互作用），并建议将分析扩展到小鼠中分析的自发性肿瘤 模型，也是一种机制。另外两个项目试图扩大我们的分析范围 在更广泛的范围内--在已经表明参与的确定基因/蛋白质子集的水平上 但需要更深入的功能调查。首先，我们将开发一种方法， 测试小家族/基因/蛋白质组的功能-每次10-50个基因的规模- 利用小片段的短发夹状RNA的条形码来探测基因组的功能。我们将使用整合素作为 我们的测试集，以开发和验证这种方法，因为广泛的先验知识，这个家庭的 细胞基质粘附受体及其参与肿瘤微环境的明确指示 交互.这种方法将被我们和其他人广泛应用于分析其他基因组， 代表了一种潜在的强大的技术发展。第二个大规模项目是利用 质谱分析的力量与基因组信息相结合，以开发描述和 肿瘤细胞外基质的分析，肿瘤微环境的关键组成部分， 对肿瘤细胞和基质细胞的行为产生深远影响。同样，这种方法的发展将 使其他人能够分析有关肿瘤微环境相互作用的各种问题。 这三个相关的项目将揭示新的信息，肿瘤细胞和基质细胞内 肿瘤与其周围的细胞外基质相互作用。已知基质对细胞有重要影响 生存、扩散和迁移。了解肿瘤ECM的性质和细胞表面受体 细胞通过其与之结合将为肿瘤的诊断和治疗开辟新的可能性。

Interactions of both tumor and stromal cells with extracellular matrix (ECM) are an important part of the influence of the microenvironment on tumor progression. Integrins are among the most prominent cell surface receptors for ECM and they have frequently been implicated in tumor progression and in metastasis. We propose three projects, all directed towards a deeper understanding of the interactions of tumor and stromal cells with the tumor microenvironment. One of these projects analyzes in depth the implications of a specific tumor-microenvironment interaction that we have recently discovered (GPR56, TG2 and their potential interactions) and proposes to extend the analyses to spontaneous tumors analyzed in mouse models as well as to the mechanistic level. The other two projects seek to extend the scope of our analyses to a broader scale - to the level of subsets of defined genes/proteins whose involvement is already indicated but in need of deeper functional investigation. In the first of these we will develop an approach to in vivo testing of the functions of small families/groups of genes/proteins - on the scale of 10-50 genes at a time - using bar-coded minilibraries of shRNA hairpins to probe the functions of gene sets. We will use integrins as our test set to develop and validate this approach because of extensive prior knowledge about this family of cell-matrix adhesion receptors and clear indications of their involvement in tumor-microenvironment interactions. This approach will be broadly applicable by us and by others to analyze other gene sets and represents a potentially powerful development of technology. The second broad-scale project is to use the power of mass spectrometry coupled with genomic information to develop methods for description and analysis of the extracellular matrix of tumors, a crucial component of the tumor microenvironment with profound effects on the behavior of both tumor and stromal cells. Again, development of this approach will enable analyses by others in the field of diverse issues concerning tumor-microenvironment interactions. These three related projects will reveal new information about how tumor cells and stromal cells within tumors interact with their surrounding extracellular matrix. Matrix is known to have major effects on cell survival, proliferation and migration. Understanding the nature of tumor ECM and the cell surface receptors through which cells bind to it will open up new possibilities for diagnosis and therapy of tumors.