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• W1982485895 abstract "The centrosome is the main microtubule-organizing center in animal cells. In dividing cells, the centrosome mediates chromosome segregation and cytokinesis; in nondividing cells, the centrosome functions as a site for microtubule polymerization. Rac1 is a guanosine triphosphatase (GTPase) that is stimulated by microtubule polymerization and contributes to cytoskeletal reorganization associated with cellular motility. Centrosome amplification can be lethal to cells, yet, in many cancers, it is associated with progression, recurrence, and poor patient survival. Godinho et al . found that centrosome amplification was associated with Rac1 signaling–mediated invasive activity in breast epithelial cells. Inducible expression of pololike kinase 4 (PLK4) or addition of dihydrocytochalasin B triggered centrosome amplification (indicated by a green fluorescent protein–tagged centrin) in the non-transformed breast epithelial cell line MCF10A. MCF10A cells cultured in a three-dimensional (3D) matrix under either condition exhibited increased formation of protrusions compared with control cells or cells induced to overexpress a truncated PLK4 mutant that retained kinase activity. Live-cell imaging showed that the protrusions were dynamic structures that initiated tracts along which multiple cells migrated out of acini (grapelike clusters of cells). Although centrosome amplification is associated with aneuploidy, cilia formation, increased p53 abundance, and altered centrosome polarization, none of these, nor changes associated with the epithelial-mesenchymal transition were involved in this invasive phenotype triggered by induction of PLK4. However, the PLK4-overexpressing cells exhibited enhanced cell scattering and defective formation of adherens junctions on a micropatterned fibronectin substrate, indicating loss of epithelial cell-cell adhesion. GTP loading of Rac1 was increased in MCF10A cells with induced overexpression of PLK4 and centrosome amplification. Inhibitors of either Rac1 or one of its targets, the Arp2/3 actin polymerization complex, prevented adherens junction defects in the micropatterned substrate assay and protrusion formation from PLK4-overexpressing MCF10A acini in 3D culture. Adding paclitaxel, a microtubule-stabilizing agent, to 3D cultures of PLK4-overexpressing MCF10A cells decreased Rac1 activation, as did knockdown of CEP192 , which promotes microtubule nucleation, which suggested that the increase in microtubule polymerization due to centrosome amplification may be triggering the increase in Rac1 activity. CEP192 knockdown also enabled proper adherens junction formation and prevented invasive acini formation in 3D cultures of PLK4-overexpressing MCF10A cells, without affecting cell viability or centrosome number. The findings indicate that centrosome amplification may be another mechanism that promotes the invasive progression of tumors. S. A. Godinho, R. Picone, M. Burute, R. Dagher, Y. Su, C. T. Leung, K. Polyak, J. S. Brugge, M. Thery, D. Pellman, Oncogene-like induction of cellular invasion from centrosome amplification. Nature 510 , 167–171 (2014). [Full Text][PubMed]" @default.
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• W1982485895 date "2014-06-10" @default.
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• W1982485895 title "Centrosomes Coordinate Cancer Invasion" @default.
• W1982485895 doi "https://doi.org/10.1126/scisignal.2005581" @default.
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