Regulation of invadopodia by mechanical signaling

Abstract

Mechanical rigidity in the tumor microenvironment is associated with a high risk of tumor formation and aggressiveness. Adhesion-based signaling driven by a rigid microenvironment is thought to facilitate invasion and migration of cancer cells away from primary tumors. Proteolytic degradation of extracellular matrix (ECM) is a key component of this process and is mediated by subcellular actin-rich structures known as invadopodia. Both ECM rigidity and cellular traction stresses promote invadopodia formation and activity, suggesting a role for these structures in mechanosensing. The presence and activity of mechanosensitive adhesive and signaling components at invadopodia further indicates the potential for these structures to utilize myosin-dependent forces to probe and remodel their ECM environments. Here, we provide a brief review of the role of adhesion-based mechanical signaling in controlling invadopodia and invasive cancer behavior.

Keywords: Actin; Adhesion; Contractility; Extracellular matrix; Invadopodia; Invasion; Mechanotransduction; Proteinases; Secretion; Signaling.

Figure 1

Invadopodia are actin-rich proteolytic protrusions that are often identified through colocalization of markers with ECM degradation. The in vitro invadopodia assay typically consists of invasive cancer cells cultured on fluoroscently-labeled ECM, in this case FITC-fibronectin-coated crosslinked gelatin. After 6-48 h, the cells are fixed and stained for molecular markers of invadopodia including actin filaments, cortactin, Arp2/3 complex, Tks5, and/or MT1-MMP [44, 45, 76, 99, 108, 109, 119]. In this case, invadopodia are identified by colocalization (purple) of actin filaments (blue) and MT1-MMP (red) using confocal microscopy imaging. Mature invadopodia are further recognized by colocalization of invadopodia markers with areas of ECM degradation (black holes in the green FITC-labeled fibronectin).

Figure 2

Adhesion-based signaling in invadopodia. Signaling through β1 integrins at and/or around the actin cores of invadopodia regulates their maturation and ability to degrade ECM with proteases such as MT1-MMP and seprase [49, 79]. Adhesion rings are strongly correlated with invadopodia activity and are dependent on adhesion and signaling components such as vinculin, paxillin, ILK, and FAK [67, 79]. In addition, invadopodia activity is also regulated by the interactions of β1 integrins with other proteins and/or complexes that include ezrin, Arg, and EGFR [83-85]. Each of these pathways is regulated by Src kinase, which is thought to control early signaling cascades necessary for invadopodia formation [25, 61]. Adhesion rings may anchor and thus stabilize nascent invadopodia and generate NM-II generated shear and tensile stresses. Actin polymerization in the core may generate protrusive stresses, similar to those identified in podosomes [78, 91-93]. Periodic fluctuations in the stresses perpendicular to the ECM surface induce oscillations of invadopodia core and ring proteins [79, 91-93]. Together, these processes may be coordinated to constantly sense and respond to local ECM rigidity. Overall, adhesion based signaling in response to ECM rigidity is an important control point for invadopodia.