Cells respond to their environment using adhesion to their surroundings, migration towards or away from signals, and reinforcement of their cytoskeletal structure to withstand mechanical stresses. These signals and responses are highly regulated in normal cells, but some differences are detected in transformed cells, such as metastatic cancer cells. For instance, we have reported oncogene-dependent alterations in adhesion, migration, and the actin cytoskeleton in Ewing sarcoma cancer cells (Chaturvedi et al., 2012). The EWS/FLI oncogene regulates expression of many adhesion-related genes including the focal adhesion component and cytoskeletal regulator zyxin. We have shown that zyxin contributes to cell adhesion, migration and actin dynamics in fibroblasts (Hoffman et al., 2006). Known to bind many other proteins, zyxin probably works as a scaffolding protein to bring proteins together at the appropriate time and place. Mechanical stimulation induces cytoskeletal reinforcement and a dramatic relocalization of zyxin and certain binding partners (Yoshigi et al., 2005; Hoffman et al., 2012). In addition to the cytoskeletal distribution, zyxin is one of several proteins that move between integrin-based adhesion sites at the cell membrane and the nucleus (Hervy et al., 2006). Zyxin is sensitive to tension that develops and dissipates along actin filaments and live cell imaging has shown zyxin's dynamic subcellular distribution (Smith et al., 2010). To better understand the cellular response to the mechanical environment, which can be greatly altered during tumor development, we are pursuing studies on the mechanism of mechanotransduction.