Discovering Microenvironments Promoting Pathological EMT using Array Technology

DESCRIPTION (provided by applicant): Lung cancer remains a leading cause of cancer death worldwide. In the US, lung cancer is responsible for 29% of cancer-related death, more than breast, colon and prostate cancers combined. Current conventional therapy- surgery, chemotherapy, radiotherapy, etc. are far from being curative for many forms of lung cancer Metastasis, the spread of tumor cells to distant sites, is a common outcome after primary tumor treatment and is the primary cause of mortality in cancerpatients. The mechanisms and the temporal progressions that lead to metastasis remain poorly defined. Recent studies have linked cancer metastasis to the improper reactivation of epithelial-mesenchymal transition (EMT). During this process, immotile polarized epithelial cells transform into highly motile apolar fibroblast-like cells. EMT induction has been linked to a number of extracellular mediators including transforming growth factor-2 (TGF-2), fibroblast growth factor-2 (FGF-2), epidermal growth factor (EGF), CTGF, insulin-like growth factor-2 (IGF-II), interleukin-1 (IL-1), hepatocyte growth factor (HGF), and Wnt ligands. Numerous studies in various pathological EMT systems provide convincing evidence that multifunctional cytokine TGF-2 signaling is aprimary inducer of EMT. In addition to these factors that have been indicated in the EMT induction, tumor microenvironments such as extra cellular matrices (ECM) may also exert powerful influence on EMT. Despite of decade's research, the role of EMT and ECM - EMT interactions in the lung carcinogenesis remain unclear. To date, researchers are still struggling to establish proper in vitro models that mimic the properties of clinically relevant microenvironments that drive EMT process. MicroStem, Inc. has developed a novel platform technology which thousands of ECMPs, growth factors and signaling molecules can be screened individually and in combination on a functionalized glass slide. Cell behavior on these conditions can be monitored and quantified. MicroStem will utilize this specialized cell array screening system to elucidate the physiologically relevant microenvironments that drives the EMT process for lung cancer cells. Our unique MicroMatrixTM array technology will serve as a novel platform to understand the interaction between tumor cells and their microenvironment (cell-cell, cell-matrix). The results of this proposal will advance the basic understanding of the natural process for tumor invasion and metastasis in lung cancer; and therefore, laying outa foundation to discover better therapeutic effects of current chemotherapies and open a new front for novel therapeutic drugs. PUBLIC HEALTH RELEVANCE: MicroStem will utilize a specialized cell array screening system to identify physiologicallyrelevant microenvironments consisting of extracellular matrix proteins, growth factors, and signaling molecules that promote epithelial mesenchymal transition (EMT) of lung cancer cells. Our unique MicroMatrixTM array technology will provide a novel platform to understand the interaction between tumor cells and their microenvironment (cell-cell, cell-matrix). The results of our proposal will advance our basic understanding on tumor invasion and metastasis in lung cancer; and therefore, laying out a foundation to discover a better therapeutic effect of current chemotherapy and open a new front for novel therapeutic drugs.