Like prisoners breaking out of jail, metastatic cancer cells tunnel through the extracellular matrix (ECM) that keeps them confined. Yu et al. reveal how an actin-interacting protein helps the cells make their escape.

Tumor cells force their way through the ECM by sprouting actin-rich extensions known as invadopodia, which contain enzymes called matrix metalloproteases to dissolve the surrounding material. Previous studies implicated the actin-polymerizing protein N-WASP in the movement of cancer cells. For example, N-WASP spurs tumor cells crawling on a two-dimensional surface to extend invadopodia.

In more realistic, three-dimensional surroundings, N-WASP also stimulated tumor cells to form invadopodia, Yu et al. showed. They found that the protein dictates a cell’s temperament. Some cancer cells are leaders that burrow into the ECM. Others are followers that rely on the path cleared by the leaders. The researchers showed that cells rarely became trailblazers if they lack N-WASP.

The protein abets tumor cells in another way, helping them deploy the matrix metalloprotease MT1-MMP. The enzyme juts from the tips of invasive protrusions, and it continually cycles between the cell membrane and the lysosome. Yu et al. determined that N-WASP re-routes MT1-MMP molecules in late endosomes—the last stop before the lysosome—and sends them back to the tips of invadopodia. N-WASP even helps retain MT1-MMP at the end of an invadopodium. The actin mesh that N-WASP induces there latches onto MT1-MMP’s cytoplasmic tail, holding the enzyme in place so that it can attack the ECM.

et al
J. Cell Biol.