Cellular Interactions with the Extracellular Matrix of the Tumor Microenvironment

Massachusetts Institute Of Technology, Cambridge MA

Investigators

Linked publications & trials

Abstract

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