Invading one step at a time: the role of invadopodia in tumor metastasis

Abstract

The ability to degrade extracellular matrix is critical for tumor cells to invade and metastasize. Recent studies show that tumor cells use specialized actin-based membrane protrusions termed invadopodia to perform matrix degradation. Invadopodia provide an elegant way for tumor cells to precisely couple focal matrix degradation with directional movement. Here we discuss several key components and regulators of invadopodia that have been uniquely implicated in tumor invasion and metastasis. Furthermore, we discuss existing and new therapeutic opportunities to target invadopodia for anti-metastasis treatment.

Figure 1. An overview of the invadopodia components and regulators discussed in this review

Twist1-induced expression of PDGFRα leads to increased Src kinase activity, which serves as a trigger for invadopodia formation. Src-mediated phosphorylation of the structural components cortactin and Tks5 and the Arg/Abl tyrosine kinase promotes invadopodia assembly. Integrin β1 serves as an adhesion mediator between invadopodia and ECM, an activator of Abl/Arg at invadopodia, a sensor of matrix stiffness to regulate invadopodia assembly, and a potential docking site for FAPα. Structural components of invadopodia, which include the actin core, are labeled in blue, proteases are labeled in purple, and regulatory components are labeled in green.

Figure 2. The role of invadopodia in metastasis progression

Tumor metastasis takes place in a series of steps: invasion into the surrounding stroma(A), intravasation into the vasculature(B), extravasation out of the vasculature(C), and colonization at distant sites. Given that invadopodia function to degrade ECM, invadopodia are thought to play critical roles during various steps of metastasis (A–C).