For example, the stroma surrounding a tumor is enriched in both type I collagen and fibronectin, creating a denser and mechanically rigid tissue compared to normal tissue. This increased rigidity enhances tumor cell proliferation and dissemination. Recent studies also indicate that physically stretching fibronectin can trigger a mechanical response pathway in normal fibroblasts. Given the increased amount of fibronectin in the stroma, these observations could suggest a potential mechanism for the mechanical response of tumor cells. There are a number of mechanical forces, aside from the change in compliance, that may impact the progression of cancer. One such force could be derived from stromal cell movements or the matrix remodeling activity of the highly contractile cells of the stroma, including fibroblasts and myofibroblasts. Myofibroblasts have been shown to differentiate from normal tissue fibroblasts, and their production and remodeling of the ECM enhances proliferation and dissemination of the tumor cells. The accumulation of stromal myofibroblasts are a defining feature of the desmoplasia most commonly associated with invasive cancers of the breast, LEE011 gastrointestinal tracts, lungs, pancreas, and squamous cell carcinomas to name a few. In addition to the high level of type I collagen production, myofibroblasts are identified by their expression of alpha-smooth muscle actin. The alpha-smooth muscle actin associates with nonmuscle myosin to form highly contractile microfilamentous units that terminate at the surface of a myofibroblast in a fibronexus. These are characteristic features of myofibroblasts and form a mechano-transduction system that functions in inside-out and outside-in force transmission. In remodeling the ECM within the stroma, the myofibroblasts produce a mechanical stimulus as they tug and pull on the fibers. This leads us to the question we address in this study. Could the applied mechanical forces generated by the remodeling of the ECM and pulling on the ECM by stromal cells contribute to the invasive properties of a tumor cell? Can they provide a ����come hither���� stimulus that encourages the tumor cells to leave the tumor? Here we report that a mechanical stimulus of pulling and releasing applied to a collagen matrix in vitro does indeed enhance the invasion of cancer cells in a fibronectin dependent manner. This ability appears to be unique to cancer cells that are known to be highly invasive, as Y-27632 dihydrochloride poorly invasive and normal cells do not respond in the same way to this stimulus. Finally, using gene silencing we determined that cofilin, a normal component of invadopodia, is required to sense this mechanical signal for enhanced invasion.