Cytoskeletal Signaling Pathways in Invadopodia Regulation

"Cytoskeletal Signaling Pathways in Invadopodia Regulation"

Breaching the basement membrane is a key step in carcinoma cell invasion. HNSCC and other cancer types frequently utilize protrusive membranous structures known as invadopodia to degrade the basement membrane as a first step towards initiating invasion into the supporting stroma. Invadopodia consist of a filamentous (F-actin) rich core that is formed in part by activation of the Arp2/3 complex. Signal transduction pathways that initiate invadopodia assembly and govern extracellular matrix degradative activity impinge on activators of Arp2/3, providing potential anti-invasive druggable targets. A long standing interest of the laboratory has been set on understanding the function of the F-actin and Arp2/3 activating protein cortactin in invadopodia and cell migration. Cortactin overexpression in HNSCC has been shown to be a reliable indicator of poor prognostic outcome and is associated with increased invasive disease. Work continues to focus on the roles of cortactin-associated kinases in regulating invadopodia maturation, actin dynamics and cell movement in 2D and 3D that effectively recapitulate the oral microenvironment. Recent work is also centered on the roles of additional actin regulatory proteins on HNSCC invadopodia function.

Representative examples of invadopodia extracellular matrix degradation activity. A. Visualization of invadopodia and corresponding gelatin matrix proteolysis. The images shows an OSC19 HNSCC cell plated on a fluorescently-labeled gelatin coated coverslip. The cell was fixed and labeled with rhodamine-conjugated phalloidin (to visualize F-actin) and anti-cortactin antibodies. Invadopodia are evident as focal cytoplasmic concentrations of F-actin and cortactin that overly areas of fluorescent gelatin clearing (dark holes in the gelatin matrix). Boxed regions show close up visualization of individual invadopodia (arrowheads). B. Volume fill visualization of invadopodia penetrating into extracellular matrix. An OSC19 cell stained as in (A) was imaged by confocal microscopy visually rendered in three dimensions to demonstrate insertion of invadopodia into the matrix (dorsal-edge) and degradation of fluorescent gelatin (ventral edge). Enlarged regions show invadopodia (arrows) and areas of matrix degradation (arrowheads).

Figure and legend adapted from