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dc.contributor.authorOlmeda, Davides_ES
dc.contributor.authorCerezo-Wallis, Danielaes_ES
dc.contributor.authorRiveiro-Falkenbach, Ericaes_ES
dc.contributor.authorPennacchi, Paula C.es_ES
dc.contributor.authorContreras-Alcalde, Martaes_ES
dc.contributor.authorIbarz, Nuriaes_ES
dc.contributor.authorCifdaloz, Metehanes_ES
dc.contributor.authorCatena, Xavieres_ES
dc.contributor.authorCalvo, Tonantzin G.es_ES
dc.contributor.authorCañón, Estelaes_ES
dc.contributor.authorAlonso-Curbelo, Direnaes_ES
dc.contributor.authorSuarez, Javieres_ES
dc.contributor.authorOsterloh, Lisaes_ES
dc.contributor.authorGraña-Castro, Osvaldoes_ES
dc.contributor.authorMulero, Franciscaes_ES
dc.contributor.authorMegías, Diegoes_ES
dc.contributor.authorCañamero, Martaes_ES
dc.contributor.authorMartínez-Torrecuadrada, Jorge Luises_ES
dc.contributor.authorMondal, Chandranies_ES
dc.contributor.authorDi Martino, Juliees_ES
dc.contributor.authorLora, Davides_ES
dc.contributor.authorMartinez-Corral, Inéses_ES
dc.contributor.authorBravo-Cordero, José J.es_ES
dc.contributor.authorMuñoz, Javieres_ES
dc.contributor.authorPuig, Susanaes_ES
dc.contributor.authorOrtiz-Romero, Pabloes_ES
dc.contributor.authorRodriguez-Peralto, José L.es_ES
dc.contributor.authorOrtega, Sagrarioes_ES
dc.contributor.authorSoengas, María S.es_ES
dc.identifier.citationNature 546: 676-680 (2017)es_ES
dc.description.abstractCutaneous melanoma is a type of cancer with an inherent potential for lymph node colonization, which is generally preceded by neolymphangiogenesis1,2,3. However, sentinel lymph node removal does not necessarily extend the overall survival of patients with melanoma4,5. Moreover, lymphatic vessels collapse and become dysfunctional as melanomas progress6,7. Therefore, it is unclear whether (and how) lymphangiogenesis contributes to visceral metastasis. Soluble and vesicle-associated proteins secreted by tumours and/or their stroma have been proposed to condition pre-metastatic sites in patients with melanoma8,9,10,11,12,13,14. Still, the identities and prognostic value of lymphangiogenic mediators remain unclear2,14. Moreover, our understanding of lymphangiogenesis (in melanomas and other tumour types) is limited by the paucity of mouse models for live imaging of distal pre-metastatic niches15. Injectable lymphatic tracers have been developed7, but their limited diffusion precludes whole-body imaging at visceral sites16. Vascular endothelial growth factor receptor 3 (VEGFR3) is an attractive ‘lymphoreporter’17 because its expression is strongly downregulated in normal adult lymphatic endothelial cells, but is activated in pathological situations such as inflammation and cancer17,18. Here, we exploit this inducibility of VEGFR3 to engineer mouse melanoma models for whole-body imaging of metastasis generated by human cells, clinical biopsies or endogenously deregulated oncogenic pathways. This strategy revealed early induction of distal pre-metastatic niches uncoupled from lymphangiogenesis at primary lesions. Analyses of the melanoma secretome and validation in clinical specimens showed that the heparin-binding factor midkine is a systemic inducer of neo-lymphangiogenesis that defines patient prognosis. This role of midkine was linked to a paracrine activation of the mTOR pathway in lymphatic endothelial cells. These data support the use of VEGFR3 reporter mice as a ‘MetAlert’ discovery platform for drivers and inhibitors of metastasis.es_ES
dc.description.sponsorshipM.S.S. is funded by grants from the Spanish Ministry of Economy and Innovation (project SAF2014-56868-R), the Asociación Española Contra el Cáncer (AECC), the Worldwide Cancer Research, an Established Investigator Award from the Melanoma Research Alliance (MRA), and a L’Oréal Paris USA-MRA Team Science Award for Woman in Scientific Research. The CNIO Proteomics Unit belongs to ProteoRed, PRB2-ISCIII, supported by grant PT13/0001. N.I. and J.M. are funded by SAF2013-45504-R (MINECO). J.M. is also supported by Ramon y Cajal Programme (MINECO) RYC-2012-10651. J.L.R.-P and P.O.-R are funded by grants FIS 2014/1737, 11/02568 and FIS 2014/01784, 11/1759, respectively, from the Spanish Ministry of Health. F.M. is funded by the AMIT Project/CDTI/CENIT Programme (MICINN), S.O. by SAF2013-44866-R (MINECO), and J.J.B.-C. by an NCI K22CA196750 grant and the TCI Young Scientist Cancer Research Award JJR Fund (P30 CA196521). J.D.M. is the recipient of a postdoctoral fellowship from the ARC Foundation and E.R.-F. from Fundación Científica de la Asociación Española Contra el Cáncer. D.C.-W. is the recipient of a predoctoral fellowship from Fundación La Caixa, and M.C.-A. and X.C. are recipients of the Immutrain Marie Skłodowska-Curie ITN Grant.es_ES
dc.publisherNature Publishing Groupes_ES
dc.titleWhole-body imaging of lymphovascular niches identifies pre-metastatic roles of midkinees_ES
dc.description.peerreviewedPeer reviewedes_ES
dc.contributor.funderMinisterio de Economía y Competitividad (España)es_ES
dc.contributor.funderAsociación Española Contra el Cánceres_ES
dc.contributor.funderWorldwide Cancer Researches_ES
dc.contributor.funderMelanoma Research Alliance (US)es_ES
dc.contributor.funderInstituto de Salud Carlos IIIes_ES
dc.contributor.funderMinisterio de Sanidad, Servicios Sociales e Igualdad (España)es_ES
dc.contributor.funderInstituto Nacional del Cáncer (España)es_ES
dc.contributor.funderIcahn School of Medicine at Mount Sinaies_ES
dc.contributor.funderArc Foundationes_ES
dc.contributor.funderFundación Científica Asociación Española Contra el Cánceres_ES
dc.contributor.funderObra Social la Caixaes_ES
dc.contributor.funderEuropean Commissiones_ES
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