Targeting invadopodia to block breast cancer metastasis

Abstract

Better understanding the mechanisms underlying the metastatic process is essential to developing novel targeted therapeutics. Recently, invadopodia have been increasingly recognized as important drivers of local invasion in metastasis. Invadopodia are basally-localized, actin-rich structures that concentrate protease activity to areas of the cell in contact with the extracellular matrix. We recently found that the transcription factor Twist1, a central regulator of the epithelial-mesenchymal transition (EMT), promotes invadopodia formation via upregulation of platelet-derived growth factor receptor (PDGFR) expression and activity. This finding, combined with other investigations into the mechanisms of invadopodia formation, reveal several novel targets for clinical inhibition of invadopodia. Here, we provide an overview of clinically-relevant targets for intervention in invadopodia, including Src signaling, PDGFR signaling, and metalloprotease activity.

Figure 1. Recent research in our lab revealed that Twist1 directly induces transcription of PDGFRα

Upregulation of PDGFRα leads to an increase in Src kinase activity that induces the formation or stabilization of invadopodia by phosphorylation of invadopodia component proteins by Src kinase. Invadopodia formation involves discrete steps in which formation of the F-actin core is an early event, followed by recruitment and phosphorylation of invadopodia component proteins like cortactin and Tks5 before proteases are recruited to the mature invadopodia. Promising targets for chemical inhibition include [1] PDGFR signaling, [2] Src kinase activity, and [3] metalloprotease activity at invadopodia (including MMP2, MMP9, and MT1-MMP).