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dc.contributor.authorLadhani, Omar-
dc.contributor.authorSánchez-Martínez, Cristina-
dc.contributor.authorOrgaz, Jose L.-
dc.contributor.authorJiménez, Benilde-
dc.contributor.authorVolpert, Olga V.-
dc.identifierdoi: 10.1593/neo.11446-
dc.identifierissn: 1522-8002-
dc.identifiere-issn: 1476-5586-
dc.identifier.citationNeoplasia 13(7): 633-642 (2011)-
dc.description.abstractMetastatic melanoma cells are highly adaptable to their in vivo microenvironment and can switch between proteasedependent mesenchymal and protease-independent amoeboid invasion to facilitate metastasis. Such adaptability can be visualized in vitro, when cells are cultured in conditions that recapitulate three-dimensional microenvironments. Using thick collagen layers in cell culture and in vivo extravasation assays, we found that pigment epithelium-derived factor (PEDF) suppressed lung extravasation of aggressive melanoma by coordinated regulation of cell shape and proteolysis. In cells grown on a thick collagen bed, PEDF overexpression and exogenous PEDF blocked the rapidly invasive, rounded morphology, and promoted an elongated, mesenchymal-like phenotype associated with reduced invasion. These changes in cell shape depended on decreased RhoA and increased Rac1 activation and were mediated by the up-regulation of Rac1-GEF, DOCK3 and down-regulation of Rac1-GAP, ARHGAP22. Surprisingly, we found that PEDF overexpression also blocked the trafficking of membrane-tethered, MT1-MMP to the cell surface through RhoA inhibition and Rac1 activation. In vivo, knockdown of Rac1 and DOCK3 or overexpression of MT1-MMP was sufficient to reverse the inhibitory effect of PEDF on extravasation. Using functional studies, we demonstrated that PEDF suppressed the rounded morphology and MT1-MMP surface localization through its antiangiongenic, 34-mer epitope and the recently identified PEDF receptor candidate, PNPLA2. Our findings unveil the coordinated regulation of cell shape and proteolysis and identify an unknown mechanism for PEDF's antimetastatic activity. © 2011 Neoplasia Press, Inc. All rights reserved.-
dc.description.sponsorshipThis work was supported by the National Institutes of Health (R01 HL68033 and R01HL077471 to O.V.) and the Ministerio de Ciencia e Innovación (SAF2007-6292 and SAF2010-19256 to B.J.). O.L. was supported by a National Institutes of Health/National Cancer Institute training grant (T32CA009560) and by the Malkin Scholars Program. J.L.O was supported by a Ministerio de Ciencia e Innovación fellowship and a SAF2007-62292 contract.-
dc.titlePigment epithelium-derived factor blocks tumor extravasation by suppressing amoeboid morphology and mesenchymal proteolysis-
dc.description.versionPeer Reviewed-
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