Cellular Interactions with the Extracellular Matrix of the Tumor Microenvironment

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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.