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dc.contributor.authorCerezo-Wallis, Daniela
dc.contributor.authorMucientes, Cynthia
dc.contributor.authorCalvo, Tonantzin G
dc.contributor.authorCañón, Estela
dc.contributor.authorAlonso-Curbelo, Direna
dc.contributor.authorIbarz, Nuria
dc.contributor.authorMuñoz, Javier
dc.contributor.authorRodriguez-Peralto, José L
dc.contributor.authorOrtiz-Romero, Pablo
dc.contributor.authorSoengas, MS 
dc.contributor.authorOrtega Jimenez, Sagrario 
dc.contributor.authorOlmeda, David 
dc.date.accessioned2022-03-24T13:45:45Z
dc.date.available2022-03-24T13:45:45Z
dc.date.issued2021-12-07
dc.identifier.citationEMBO Mol Med . 2021;13(12):e12924es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/13816
dc.description.abstractLong-range communication between tumor cells and the lymphatic vasculature defines competency for metastasis in different cancer types, particularly in melanoma. Nevertheless, the discovery of selective blockers of lymphovascular niches has been compromised by the paucity of experimental systems for whole-body analyses of tumor progression. Here, we exploit immunocompetent and immunodeficient mouse models for live imaging of Vegfr3-driven neolymphangiogenesis, as a versatile platform for drug screening in vivo. Spatiotemporal analyses of autochthonous melanomas and patient-derived xenografts identified double-stranded RNA mimics (dsRNA nanoplexes) as potent inhibitors of neolymphangiogenesis, metastasis, and post-surgical disease relapse. Mechanistically, dsRNA nanoplexes were found to exert a rapid dual action in tumor cells and in their associated lymphatic vasculature, involving the transcriptional repression of the lymphatic drivers Midkine and Vegfr3, respectively. This suppressive function was mediated by a cell-autonomous type I interferon signaling and was not shared by FDA-approved antimelanoma treatments. These results reveal an alternative strategy for targeting the tumor cell-lymphatic crosstalk and underscore the power of Vegfr3-lymphoreporters for pharmacological testing in otherwise aggressive cancers.es_ES
dc.description.sponsorshipThe authors thank previous and present colleagues in the CNIO Melanoma Group, particularly Damia Tormo and Lisa Osterloh for help and support at the initial stages of this study; Jose A Esteban (CSIC-UAM) for critical reading of this manuscript; Lionel Larue (INSERM; France) and Martin McMahon (Hunstman Cancer Center, USA) for the Tyr:CreERT2 and BrafCA mouse strains, respectively; and Ignacio Melero at Hospital Clinico, Pamplona, Spain, for Ifnar1-deficient mice. The authors thank Isabel Blanco, Soraya Ruiz, and Virginia Granda (CNIO-Animal Facility Unit), Diego Megias (CNIO-Confocal Unit), and Eduardo Jose Caleiras and Patricia Gonzalez (CNIO-Histopathology Unit) for technical assistance. M.S.S. is funded by grants from the Spanish Ministry of Economy and Innovation (SAF2017-89533-R), the Asociacion Espanola Contra el Cancer (AECC), Fundacion La Caixa, and an Established Investigator Award by the Melanoma Research Alliance (MRA). D.O. is funded by grants from the Spanish Ministry of Health (AES-PIS PI18/1057) and "Beca Leonardo a Investigadores y Creadores Culturales 2018 de la Fundacion BBVA". The CNIO Proteomics Unit belongs to ProteoRed, PRB3-ISCIII, supported by grant PT17/0019. S.O. is also supported by a grant from the Spanish Ministry of Economy, Industry and Competitiveness (BFU2015-71376-R).es_ES
dc.language.isoenges_ES
dc.publisherWiley es_ES
dc.type.hasVersionVoRes_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshMelanoma es_ES
dc.subject.meshRNA, Double-Stranded es_ES
dc.subject.meshAnimals es_ES
dc.subject.meshHumans es_ES
dc.subject.meshMice es_ES
dc.subject.meshMice, Nude es_ES
dc.subject.meshSignal Transduction es_ES
dc.titleLive imaging of neolymphangiogenesis identifies acute antimetastatic roles of dsRNA mimics.es_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.identifier.pubmedID34762341es_ES
dc.format.volume13es_ES
dc.format.number12es_ES
dc.format.pagee12924es_ES
dc.identifier.doi10.15252/emmm.202012924es_ES
dc.contributor.funderAsociación Española Contra el Cáncer es_ES
dc.contributor.funderFundación La Caixa es_ES
dc.contributor.funderMelanoma Research Alliance es_ES
dc.contributor.funderInstituto de Salud Carlos III es_ES
dc.contributor.funderFundación BBVA es_ES
dc.contributor.funderMinisterio de Economía, Industria y Competitividad (España) es_ES
dc.description.peerreviewedes_ES
dc.identifier.e-issn1757-4684es_ES
dc.relation.publisherversionhttps://doi.org/10.15252/emmm.202012924.es_ES
dc.identifier.journalEMBO molecular medicinees_ES
dc.repisalud.institucionCNIOes_ES
dc.repisalud.orgCNIOCNIO::Grupos de investigación::Grupo de Melanomaes_ES
dc.rights.accessRightsopen accesses_ES
dc.relation.projectFISinfo:eu-repo/grantAgreement/SAF2017-89533-Res_ES
dc.relation.projectFISinfo:eu-repo/grantAgreement/AES-PIS PI18/1057es_ES
dc.relation.projectFISinfo:eu-repo/grantAgreement/BFU2015-71376-Res_ES
dc.relation.projectFISinfo:eu-repo/grantAgreement/ PT17/0019es_ES


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