title: Diaphanous-related formins are required for invadopodia formation and invasion of breast tumor cells.
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.
authors.affiliation: Research Center, Institut Curie, Paris, France.
authors.forename: Floria
authors.initials: F
authors.lastname: Lizárraga
authors.forename: Renaud
authors.initials: R
authors.lastname: Poincloux
authors.forename: Maryse
authors.initials: M
authors.lastname: Romao
authors.forename: Guillaume
authors.initials: G
authors.lastname: Montagnac
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Le Dez
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bonne
authors.forename: Guillem
authors.initials: G
authors.lastname: Rigaill
authors.forename: Graça
authors.initials: G
authors.lastname: Raposo
authors.forename: Philippe
authors.initials: P
authors.lastname: Chavrier
mesh_terms: D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D001485:Basement Membrane / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D045744:Cell Line, Tumor; D051356:Cortactin / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D000080865:Formins; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D009361:Neoplasm Invasiveness
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; C495868:CTTN protein, human; D051356:Cortactin; C108962:DIAPH1 protein, human; D000080865:Formins; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14