Filopodia-independent roles of the actin bundling protein fascin in promoting cell motility

Abstract

Fascin is an actin bundling protein whose overexpression has in recent years been systematically linked to increased metastasis and poor outcome in cancer patients. It is well established that fascin expression correlates with enhanced cell migration; however, the underlying mechanisms are poorly understood. We combined various methods of high-resolution live cell imaging and computational analysis to investigate the role of fascin in increasing cell motility. We found that fascin promotes collective migration in normal epithelial cells and that this behavior is in agreement with protrusive activities at the single cell level. Traction force measurements indicated that fascin expression level is negatively correlated with traction stress levels and that a cell expressing high levels of fascin protrudes over longer distances than cells with lower levels. Together this led to the hypothesis that fascin distributes cell traction more efficiently, which lowers the load on individual adhesions and actin filaments growing against increasing membrane tension during one protrusion cycle. Measurements of adhesion formation and maturation indicate that fascin expression indeed promotes nascent adhesion formation over a wide area behind the leading edge. In metastatic cells with high fascin expression, we observed decreased invasion upon fascin knock down. These observations demonstrate a role for fascin in promoting cell motility in normal and neoplastic cells, in part by templating nascent adhesions at the leading edge.