Interactions of both tumor and stromal cells with extracellular matrix (ECM) are an important part of theinfluence of the microenvironment on tumor progression. Integrins are among the most prominent cellsurface 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 andstromal cells with the tumor microenvironment. One of these projects analyzes in depth the implications of aspecific tumor-microenvironment interaction that we have recently discovered (GPR56, TG2 and theirpotential interactions) and proposes to extend the analyses to spontaneous tumors analyzed in mousemodels as well as to the mechanistic level. The other two projects seek to extend the scope of our analysesto a broader scale - to the level of subsets of defined genes/proteins whose involvement is already indicatedbut in need of deeper functional investigation. In the first of these we will develop an approach to in vivotesting 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 asour test set to develop and validate this approach because of extensive prior knowledge about this family ofcell-matrix adhesion receptors and clear indications of their involvement in tumor-microenvironmentinteractions. This approach will be broadly applicable by us and by others to analyze other gene sets andrepresents a potentially powerful development of technology. The second broad-scale project is to use thepower of mass spectrometry coupled with genomic information to develop methods for description andanalysis of the extracellular matrix of tumors, a crucial component of the tumor microenvironment withprofound effects on the behavior of both tumor and stromal cells. Again, development of this approach willenable 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 withintumors interact with their surrounding extracellular matrix. Matrix is known to have major effects on cellsurvival, proliferation and migration. Understanding the nature of tumor ECM and the cell surface receptorsthrough which cells bind to it will open up new possibilities for diagnosis and therapy of tumors.
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