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dc.contributor.authorPerera, U.
dc.contributor.authorGillett, C.
dc.contributor.authorLaw, A-L.
dc.contributor.authorSharma, V. P.
dc.contributor.authorWang, J.
dc.contributor.authorMosis, F.
dc.contributor.authorDe Piano, M.
dc.contributor.authorMonypenny, J.
dc.contributor.authorWoodman, N.
dc.contributor.authorMouneimne, G.
dc.contributor.authorVan Hemelrijck, M.
dc.contributor.authorCao, Y.
dc.contributor.authorCondeelis, J.
dc.contributor.authorKrause, M.
dc.contributor.authorCarmona, Guillaume
dc.contributor.authorNaba, Alexandra
dc.contributor.authorWyckoff, Jeffrey
dc.contributor.authorBalsamo, Michele
dc.contributor.authorMcConnell, Russell E.
dc.contributor.authorHynes, Richard O.
dc.contributor.authorGertler, Frank
dc.date.accessioned2016-11-08T17:27:25Z
dc.date.available2016-11-08T17:27:25Z
dc.date.issued2016-03
dc.date.submitted2016-01
dc.identifier.issn0950-9232
dc.identifier.issn1476-5594
dc.identifier.urihttp://hdl.handle.net/1721.1/105260
dc.description.abstractCancer invasion is a hallmark of metastasis. The mesenchymal mode of cancer cell invasion is mediated by elongated membrane protrusions driven by the assembly of branched F-actin networks. How deregulation of actin regulators promotes cancer cell invasion is still enigmatic. We report that increased expression and membrane localization of the actin regulator Lamellipodin correlate with reduced metastasis-free survival and poor prognosis in breast cancer patients. In agreement, we find that Lamellipodin depletion reduced lung metastasis in an orthotopic mouse breast cancer model. Invasive 3D cancer cell migration as well as invadopodia formation and matrix degradation was impaired upon Lamellipodin depletion. Mechanistically, we show that Lamellipodin promotes invasive 3D cancer cell migration via both actin-elongating Ena/VASP proteins and the Scar/WAVE complex, which stimulates actin branching. In contrast, Lamellipodin interaction with Scar/WAVE but not with Ena/VASP is required for random 2D cell migration. We identified a phosphorylation-dependent mechanism that regulates selective recruitment of these effectors to Lamellipodin: Abl-mediated Lamellipodin phosphorylation promotes its association with both Scar/WAVE and Ena/VASP, whereas Src-dependent phosphorylation enhances binding to Scar/WAVE but not to Ena/VASP. Through these selective, regulated interactions Lamellipodin mediates directional sensing of epidermal growth factor (EGF) gradients and invasive 3D migration of breast cancer cells. Our findings imply that increased Lamellipodin levels enhance Ena/VASP and Scar/WAVE activities at the plasma membrane to promote 3D invasion and metastasis.en_US
dc.description.sponsorshipVirginia and D.K. Ludwig Fund for Cancer Research (Postdoctoral fellowship)en_US
dc.description.sponsorshipKing's College London (Overseas Research PhD Studentship (KORS))en_US
dc.description.sponsorshipNational Cancer Institute (U.S.) (U54-CA112967)en_US
dc.description.sponsorshipNational Cancer Institute (U.S.) (U54-CA163109)en_US
dc.description.sponsorshipLudwig Center for Molecular Oncology at MITen_US
dc.description.sponsorshipDavid H. Koch Institute for Integrative Cancer Research at MIT (Support Grant P30-CA14051)en_US
dc.description.sponsorshipNational Cancer Institute (U.S.) (Koch Institute Support Grant P30-CA14051)en_US
dc.description.sponsorshipBiotechnology and Biological Sciences Research Council (Great Britain) (BB/F011431/1)en_US
dc.description.sponsorshipBiotechnology and Biological Sciences Research Council (Great Britain) (BB/J000590/1)en_US
dc.description.sponsorshipBiotechnology and Biological Sciences Research Council (Great Britain) (BB/N000226/1)en_US
dc.description.sponsorshipWellcome Trust (London, England) (082907/Z/07/Z)en_US
dc.language.isoen_US
dc.publisherSpringer Natureen_US
dc.relation.isversionofhttp://dx.doi.org/10.1038/onc.2016.47en_US
dc.rightsCreative Commons Attribution 4.0 International Licenseen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.sourceNatureen_US
dc.titleLamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVEen_US
dc.typeArticleen_US
dc.identifier.citationCarmona, G., U. Perera, C. Gillett, A. Naba, A.-L. Law, V. P. Sharma, J. Wang, et al. “Lamellipodin Promotes Invasive 3D Cancer Cell Migration via Regulated Interactions with Ena/VASP and SCAR/WAVE.” Oncogene 35, no. 39 (March 21, 2016): 5155–5169.en_US
dc.contributor.departmentDavid H. Koch Institute for Integrative Cancer Research at MITen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.mitauthorCarmona, Guillaume
dc.contributor.mitauthorNaba, Alexandra
dc.contributor.mitauthorWyckoff, Jeffrey
dc.contributor.mitauthorBalsamo, Michele
dc.contributor.mitauthorMcConnell, Russell E.
dc.contributor.mitauthorHynes, Richard O.
dc.contributor.mitauthorGertler, Frank
dc.relation.journalOncogeneen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsCarmona, G.; Perera, U.; Gillett, C.; Naba, A.; Law, A.-L.; Sharma, V. P.; Wang, J.; Wyckoff, J.; Balsamo, M.; Mosis, F.; De Piano, M.; Monypenny, J.; Woodman, N.; McConnell, R. E.; Mouneimne, G.; Van Hemelrijck, M.; Cao, Y.; Condeelis, J.; Hynes, R. O.; Gertler, F. B.; Krause, M.en_US
dspace.embargo.termsNen_US
dc.identifier.orcidhttps://orcid.org/0000-0001-5063-8502
dc.identifier.orcidhttps://orcid.org/0000-0001-7603-8396
dc.identifier.orcidhttps://orcid.org/0000-0003-3214-4554
dspace.mitauthor.errortrue
mit.licensePUBLISHER_CCen_US


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