Fascin: Invasive filopodia promoting metastasis

Abstract

Fascin is an evolutionarily conserved actin bundling protein that localizes to microspikes, filopodia and actin-based protrusions underneath the plasma membrane. fascin has received a lot of attention among cytoskeletal proteins because multiple clinical studies have implicated its expression in cancer progression and metastasis. this may be because fascin is not normally expressed in epithelial tissues and when it is upregulated as a part of a program of cancer cell epithelial to mesenchymal progression it confers special motility and invasion properties on cancer cells. in normal adult tissues, fascin expression is high in neurons and dendritic cells; both cell types have striking large filopodia and are highly motile. it is not clear how fascin promotes invasive motility in cancer cells, but many studies have implicated filopodia formation in motility and we have recently provided new evidence that fascin stabilizes actin bundles in invasive foot structures termed invadopodia in cancer cells Figure 1.1 Here we review some of the evidence implicating fascin in motility, invasion and cancer aggressiveness, and we speculate that by stabilizing actin, fascin provides cells with powerful invasive properties that may confer increased metastatic potential.

Keywords: cancer; fascin; filopodia; invadopodia; invasion; metastasis; microspikes; migration; motility; podosomes.

Figure 1

Fascin and p34 (Arp2/3 complex) colocalized at invadopodia. A375MM human metastatic melanoma cells plated on FITC-gelatin for 16 hours, fixed and stained with antibody as indicated.

Figure 2

A model showing fascin stabilizing actin bundles in an invasive cell migrating in the 3D environment of the tumor stroma. Sites of matrix remodeling can occur at protrusions or at other sites along the periphery of the cell, wherever the extracellular matrix (ECM) impedes cell migration and thus needs to be degraded for the cell to pass through. CHL-1 melanoma cells made both actin-rich spots and long thin filopod-like protrusions in matrigel-collagen gels. We have drawn fascin-actin bundles here close to the plasma membrane, but it is possible that they could form a core inside of the branched actin networks rather than or additional to a shell around them. Arp2/3 complex and cortactin contribute to formation of branched actin networks and may also assist in membrane trafficking to and from sites of ECM remodeling. Integrins allow the cell to grab and pull against the ECM to aid migration.