Editors' ChoiceCancer

Breaking Down the Invasion

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Science Signaling  24 Jun 2014:
Vol. 7, Issue 331, pp. ec173
DOI: 10.1126/scisignal.2005624

Metastatic cancer cells form actin-rich cellular protrusions called invadopodia that are involved in degrading the extracellular matrix. Invadopodia are dynamic structures that form and retract, and the actin-polymerizing protein cortactin localizes to invadopodia and promotes their formation. Moshfegh et al. found that the Rho family guanosine triphosphatase (GTPase) Rac1, along with an upstream activator (the guanine nucleotide exchange factor TrioGEF) and a downstream effector (the kinase Pak1), promoted invadopodia retraction. In various metastatic breast cancer cell lines, including MTLn3 and MDA-MB-231 adenocarcinoma cells, knockdown of Rac1, Pak1, or TrioGEF increased the ability of these cells to degrade matrix. Imaging of MTLn3 or MDA-MB-231 cells with a biosensor of Rac1 activity indicated that Rac1 was not active in the core of invadopodia, which was marked by the presence of cortactin. Laser uncaging of a photoactivatable form of Rac1 in already-formed invadopodia in MTLn3 cells triggered the disappearance of the invadopodia. Phosphorylation of cortactin by Pak1 triggers the dissociation of cortactin from actin, and uncaging photoactivatable Rac1 did not trigger the disappearance of invadopodia in cells in which Pak1 was knocked down or in cells expressing a form of cortactin that cannot be phosphorylated by Pak1. TrioGEF was localized in invadopodia and activated Rac1 in these cellular protrusions. Furthermore, the matrix-degrading ability of MTLn3 cells was decreased by overexpression of a constitutively active form of TrioGEF and increased by that of a dominant-negative form. MTLn3 cells in which Rac1, Pak1, or TrioGEF was knocked down showed decreased Matrigel invasion, three-dimensional (3D) motility, and degradation of a 3D collagen-Matrigel matrix. Thus, a signaling pathway targets cortactin to control invadopodia retraction.

Y. Moshfegh, J. J. Bravo-Cordero, V. Miskolci, J. Condeelis, L. Hodgson, A Trio–Rac1–Pak1 signalling axis drives invadopodia disassembly. Nat. Cell Biol. 16, 574 – 586 (2014). [PubMed]

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