Artym et al. reveal that a type of ECM commonly found in advanced metastatic tumors is a potent inducer of invasive cell protrusions.
Cells remodel and invade the ECM by forming invadopodia, actin-rich protrusions containing matrix metalloproteinases such as MT1-MMP. Studies using artificial gelatin-based matrices have shown that increasing ECM stiffness enhances invadopodia formation, but how more physiologically relevant matrices influence the process is unclear. Advanced-stage tumors often deposit large amounts of fibrillar collagen into their stroma, so Artym et al. tested the ability of high-density fibrillar collagen (HDFC) matrices to induce invadopodia.
HDFC matrices induced numerous cancer cell lines, and even normal fibroblasts, to form many more invadopodia than they did on stiffer gelatin-based matrices. Unlike the protrusions formed on gelatin, HDFC-induced invadopodia didn’t require the activity of any growth factors for their formation. Nor did their induction involve any changes in gene or protein expression. Instead, the researchers found, HDFC stimulated invadopodia formation by activating the collagen-binding integrin α2β1 and a downstream network of signaling proteins that regulate cell adhesion and the actin cytoskeleton. For example, HDFC stimulated phosphorylation of the integrin-activating protein kindlin2. Knocking down kindlin2, or expressing a nonphosphorylatable version, inhibited invadopodia induction, whereas phosphomimetic kindlin2 mutants stimulated invadopodia formation.
The dense collagen fibers found in malignant tumors may therefore stimulate ECM remodeling and cell invasion. Lead author Vira Artym now wants to identify ways of blocking invadopodia formation in tumor cells without affecting the function of healthy cells.
Text by Ben Short