Tumor Cellular and Microenvironmental Cues Controlling Invadopodia Formation

Abstract

During the metastatic progression, invading cells might achieve degradation and subsequent invasion into the extracellular matrix (ECM) and the underlying vasculature using invadopodia, F-actin-based and force-supporting protrusive membrane structures, operating focalized proteolysis. Their formation is a dynamic process requiring the combined and synergistic activity of ECM-modifying proteins with cellular receptors, and the interplay with factors from the tumor microenvironment (TME). Significant advances have been made in understanding how invadopodia are assembled and how they progress in degradative protrusions, as well as their disassembly, and the cooperation between cellular signals and ECM conditions governing invadopodia formation and activity, holding promise to translation into the identification of molecular targets for therapeutic interventions. These findings have revealed the existence of biochemical and mechanical interactions not only between the actin cores of invadopodia and specific intracellular structures, including the cell nucleus, the microtubular network, and vesicular trafficking players, but also with elements of the TME, such as stromal cells, ECM components, mechanical forces, and metabolic conditions. These interactions reflect the complexity and intricate regulation of invadopodia and suggest that many aspects of their formation and function remain to be determined. In this review, we will provide a brief description of invadopodia and tackle the most recent findings on their regulation by cellular signaling as well as by inputs from the TME. The identification and interplay between these inputs will offer a deeper mechanistic understanding of cell invasion during the metastatic process and will help the development of more effective therapeutic strategies.

Keywords: cell invasion; cytoskeleton; extracellular matrix; invadopodia; metastasis; receptors; tumor microenvironment.

FIGURE 1

The main receptors involved in the formation and activities of invadopodia. Schematic illustration of the main cellular receptors driving invadopodia in cancer cells: (A) The family of tyrosine kinase receptors includes epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor α (PDGFRα), Tyrosine-Protein Kinase Met (Met); (B) The family of G-protein-coupled receptors (GPCR) includes lysophosphatidic acid receptors (LPAR), endothelin-1 receptors (ET-1R), kisspeptin receptors (KISS1R), C-X-C Motif Chemokine Receptor 4 (CXCR4), C-C Motif Chemokine Receptor 3 (CCR3); (C) The transforming growth factor β (TGFβ) receptors family includes TGFβR1 and TGFβR2; (D) The family of integrins includes the β1 and β3 subunits. The plot was created using BioRender (app.biorender.com).

FIGURE 2

Signals deriving from the tumor microenvironment (TME) affecting invadopodia formation and activity. Inputs derived from the TME include the extracellular matrix (ECM) composition, such as collagens, laminin, fibronectin; the interaction with stromal cells, specifically activated fibroblasts, and macrophages; mechanical signals such as matrix stiffness, topography, tension, viscosity and the mechanical interplay with the nucleus; metabolic conditions typical of cancer cells, such as extracellular acidosis and intracellular low tensions oxygen (hypoxia). The plot was created using BioRender (app.biorender.com).