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dc.contributor.authorGarcía-Silva, Susana
dc.contributor.authorBenito-Martín, Alberto
dc.contributor.authorNogués, Laura
dc.contributor.authorHernández-Barranco, Alberto
dc.contributor.authorMazariegos, Marina S.
dc.contributor.authorSantos, Vanesa
dc.contributor.authorHergueta-Redondo, Marta
dc.contributor.authorXiménez-Embún, Pilar
dc.contributor.authorKataru, Raghu P.
dc.contributor.authorLopez, Ana Amor
dc.contributor.authorMerino, Cristina
dc.contributor.authorSánchez-Redondo, Sara
dc.contributor.authorGraña-Castro, Osvaldo 
dc.contributor.authorMatei, Irina
dc.contributor.authorNicolás-Avila, José Ángel
dc.contributor.authorTorres-Ruiz, Raúl
dc.contributor.authorRodríguez-Perales, Sandra
dc.contributor.authorMartínez, Lola
dc.contributor.authorPérez-Martínez, Manuel
dc.contributor.authorMata, Gadea
dc.contributor.authorSzumera-Ciećkiewicz, Anna
dc.contributor.authorKalinowska, Iwona
dc.contributor.authorSaltari, Annalisa
dc.contributor.authorMartínez-Gómez, Julia M.
dc.contributor.authorHogan, Sabrina A.
dc.contributor.authorSaragovi, H. Uri
dc.contributor.authorOrtega, Sagrario
dc.contributor.authorGarcia-Martin, Carmen
dc.contributor.authorBoskovic, Jasminka 
dc.contributor.authorLevesque, Mitchell P.
dc.contributor.authorRutkowski, Piotr
dc.contributor.authorHidalgo, Andrés 
dc.contributor.authorMuñoz, Javier
dc.contributor.authorMegías, Diego
dc.contributor.authorMehrara, Babak J.
dc.contributor.authorLyden, David
dc.contributor.authorPeinado Selgas, Hector
dc.identifier.citationNat Cancer. 2021;es_ES
dc.description.abstractSecreted extracellular vesicles (EVs) influence the tumor microenvironment and promote distal metastasis. Here we analyzed the involvement of melanoma-secreted EVs in lymph node pre-metastatic niche formation in murine models. We found that small EVs (sEVs) derived from metastatic melanoma cell lines were enriched in nerve growth factor (NGF) receptor (NGFR, p75NTR), spread through the lymphatic system and were taken up by lymphatic endothelial cells, reinforcing lymph node metastasis. Remarkably, sEVs enhanced lymphangiogenesis and tumor cell adhesion by inducing ERK kinase, nuclear factor (NF)-κB activation and intracellular adhesion molecule (ICAM)-1 expression in lymphatic endothelial cells. Importantly, ablation or inhibition of NGFR in sEVs reversed the lymphangiogenic phenotype, decreased lymph node metastasis and extended survival in pre-clinical models. Furthermore, NGFR expression was augmented in human lymph node metastases relative to that in matched primary tumors, and the frequency of NGFR+ metastatic melanoma cells in lymph nodes correlated with patient survival. In summary, we found that NGFR is secreted in melanoma-derived sEVs, reinforcing lymph node pre-metastatic niche formation and metastasis.es_ES
dc.description.sponsorshipwe apologize to those authors whose work could not be cited due to size restrictions. We thank M. S. Soengas and the members of her laboratory for melanoma cells, primary melanocyte preparations and helpful discussions. We thank M. Detmar and S. Proulx for the mouse B16-F1R2 cell line. We are grateful to M. Yañez-Mo and M. Valés for antibodies against sEV markers. We thank D. Grela and A. Escobar from IESMAT for their support with the Zetasizer analysis. We thank G. Roncador, L. Maestre and J. L. Martinez Torrecuadrada for their help with the development and characterization of anti-NGFR antibodies and C. Villarroya Beltri for her help in flow cytometry analysis. This work was funded by the Starr Cancer Consortium (B.J.M., D.L. and H.P.), the US NIH (R01-CA169416), the Nancy C. and Daniel P. Paduano Foundation, the Children’s Cancer and Blood Foundation (H.P. and D.L.), the Melanoma Research Alliance, the Feldstein Foundation, RETOS SAF2017-82924-R (AEI/10.13039/501100011033/FEDER-UE), the Fundación Ramón Areces, the Fundación Bancaria ‘la Caixa’ (HR18-00256), ATRES-MEDIA AXA Foundation (CONSTANTES Y VITALES, una iniciativa de laSexta y Fundación AXA) and the Fundación Científica AECC (LABAE19027PEIN, GCB15152978SOEN-HP) (H.P.), the Malcolm Hewitt Wiener Foundation, the AHEPA Fifth District Cancer Research Foundation, the Hartwell Foundation and the Manning Foundation (D.L.). We are also grateful for the support of the Translational Network for the Clinical Application of Extracellular Vesicles (TeNTaCLES), RED2018-102411-T (AEI/10.13039/501100011033), the Ramón y Cajal Programme, the FERO Foundation, Comunidad of Madrid 2017-T2/BMD6026 (L.N.) and La Caixa Foundation (ID100010434, fellowship LCF/BQ/ES17/11600007) (A.H.-B.). The CNIO, certified as a Severo Ochoa Excellence Centre, is supported by the Spanish government through the ISCIII.es_ES
dc.publisherSpringuer Naturees_ES
dc.titleMelanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis through an NGFR-dependent mechanismes_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.contributor.funderStarr Cancer Consortiumes_ES
dc.contributor.funderNational Institutes of Health (Estados Unidos)es_ES
dc.contributor.funderPaduano Foundationes_ES
dc.contributor.funderChildren’s Cancer and Blood Foundationes_ES
dc.contributor.funderMelanoma Research Alliancees_ES
dc.contributor.funderFeldstein Foundationes_ES
dc.contributor.funderFundación Ramón Areceses_ES
dc.contributor.funderFundación La Caixaes_ES
dc.contributor.funderAsociación Española Contra el Cánceres_ES
dc.contributor.funderMalcolm Hewitt Wiener Foundationes_ES
dc.contributor.funderAHEPA Fifth District Cancer Research Foundationes_ES
dc.contributor.funderHartwell Foundation and the Manning Foundationes_ES
dc.contributor.funderTranslational Network for the Clinical Application of Extracellular Vesicles (TeNTaCLES)es_ES
dc.contributor.funderCentro Nacional de Investigaciones Oncológicas (Severo Ochoa Excellence Centre)es_ES
dc.contributor.funderFundación AXA
dc.identifier.journalNature Canceres_ES
dc.repisalud.orgCNIOCNIO::Grupos de investigación::Grupo de Microambiente y Metástasises_ES

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Atribución-NoComercial-CompartirIgual 4.0 Internacional
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