Diaphanous-Related Formins Are Required for Invadopodia Formation and Invasion of Breast Tumor Cells

¹Research Center and ²Department of Translational Research, Institut Curie; ³Membrane and Cytoskeleton Dynamics and ⁴Structure and Membrane Compartments, Centre National de la Recherche Scientifique (CNRS), UMR144; ⁵Institut Pasteur, Ultrastructural Microscopy Platform; and ⁶UMR AgroParisTech/INRA 518, Statistics and Genome Team, Paris, France

^* To whom correspondence should be addressed. E-mail: Philippe.Chavrier{at}curie.fr.

	Abstract

Proteolytic degradation of the extracellular matrix by metastatic tumor cells is initiated by the formation of invadopodia, i.e., actin-driven filopodia-like membrane protrusions endowed with matrix-degradative activity. A signaling cascade involving neural Wiskott-Aldrich syndrome protein and the Arp2/3 actin nucleating complex is involved in actin assembly at invadopodia. Yet, the mechanism of invadopodia formation is poorly understood. Based on their role as actin nucleators in cytoskeletal rearrangements, including filopodia formation, we examined the function of Diaphanous-related formins (DRF) in invadopodia formation and invasion by breast tumor cells. Using small interfering RNA silencing of protein expression in highly invasive MDA-MB-231 breast adenocarcinoma cells, we show that three members of the DRF family (DRF1–DRF3) are required for invadopodia formation and two-dimensional matrix proteolysis. We also report that invasion of a three-dimensional Matrigel matrix involves filopodia-like protrusions enriched for invadopodial proteins, including membrane type 1 matrix metalloproteinase, which depend on DRFs for their formation. These data identify DRFs as critical components of the invasive apparatus of tumor cells in two-dimensional and three-dimensional matrices and suggest that different types of actin nucleators cooperate during the formation of invadopodia. [Cancer Res 2009;69(7):OF1–9]

Key Words: formins, Rho GTPases, MT1-MMP, invadopodia, invasion

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