A long-term goal of our laboratory is to identify novel molecular targets for therapeutic strategies to inhibit invasive tumor growth and metastasis. In the epidermis of the skin, epithelial cells adhere to a specialized extracellular matrix (ECM) that prevents them from migrating into adjacent tissues. Cell adhesion to the ECM is also required for epithelial cell survival, since loss of adhesion leads to apoptotic cell death. During skin tumorigenesis, transformed epithelial cells secrete matrix metalloproteases, such as MMP-9, which can promote tumor growth and cell invasion by both degrading the ECM and liberating ECM-bound growth factors. In addition, invasive cancer cells become resistant to apoptosis, enhancing their ability to survive as they metastasize to distal tissues. Integrins are the major receptors for cell adhesion to the ECM, and some integrins can transmit signals into the cell that regulate MMP gene expression, cell migration, and cell survival. A major focus of our laboratory is on defining these integrin-mediated signal transduction pathways. Integrin α3ß1 provides a useful model for our studies, since this integrin is expressed in many cancer cell types and has been implicated in promoting carcinoma growth and invasion. We have established "MK" cell lines from epidermis of mice that lack integrin α3ß1, due to null mutation of the α3 gene, and from normal mice as controls. We have also established several variants of these MK cell lines representing different stages of the cellular transformation process. Through comparative analyses of these cell lines, we have determined that integrin α3ß1 plays important roles in MMP-9 gene expression (Iyer et al., 2005), in regulating cell migration (Choma et al., 2004), and in promoting cell survival (Manohar et al., 2004). We are using adenoviral/retroviral constructs and pharmacological inhibitors to perturb focal adhesion kinase (FAK) and other key intracellular signaling proteins to determine their importance in integrin-mediated MMP-9 gene expression, cell migration, and cell survival. In addition, we are developing several in vivo tumor models in order to link integrin-mediated signaling pathways with tumor growth, progression, and cell invasion, and to determine whether perturbation of these pathways is an effective way to inhibit invasive tumor growth. In one such model, we are testing the tumorigenic and metastatic potential of the MK cell lines following injection into immuno-compromised mice. In a second approach, we are studying tumor growth in mice that harbor mutations in genes for key integrins and/or signaling proteins.