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dc.contributor.authorSegura Collar, Berta
dc.contributor.authorGarranzo Asensio, María
dc.contributor.authorHerranz Sánchez, Beatriz
dc.contributor.authorHernández SanMiguel, Esther
dc.contributor.authorCejalvo, Teresa
dc.contributor.authorS. Casas, Bárbara
dc.contributor.authorMatheu, Ander
dc.contributor.authorPérez Núñez, Ángel
dc.contributor.authorSepúlveda Sánchez, Juan M.
dc.contributor.authorHernández Laín, Aurelio
dc.contributor.authorPalma, Verónica
dc.contributor.authorGargini, Ricardo
dc.contributor.authorSánchez Gómez, Pilar
dc.date.accessioned2021-06-17T09:58:13Z
dc.date.available2021-06-17T09:58:13Z
dc.date.issued2021
dc.identifier.issn0008-5472spa
dc.identifier.urihttp://hdl.handle.net/10641/2330
dc.description.abstractThe extraordinary plasticity of glioma cells allows them to contribute to different cellular compartments in tumor vessels, reinforcing the vascular architecture. It was recently revealed that targeting glioma-derived pericytes, which represent a big percentage of the mural cell population in aggressive tumors, increases the permeability of the vessels and improves the efficiency of chemotherapy. However, the molecular determinants of this transdifferentiation process have not been elucidated. Here we show that mutations in EGFR stimulate the capacity of glioma cells to function as pericytes in a BMX- (bone marrow and X-linked) and SOX9-dependent manner. Subsequent activation of platelet-derived growth factor receptor beta in the vessel walls of EGFR-mutant gliomas stabilized the vasculature and facilitated the recruitment of immune cells. These changes in the tumor microenvironment conferred a growth advantage to the tumors but also rendered them sensitive to pericyte-targeting molecules such as ibrutinib or sunitinib. In the absence of EGFR mutations, high-grade gliomas were enriched in blood vessels, but showed a highly disrupted blood–brain barrier due to the decreased BMX/SOX9 activation and pericyte coverage, which led to poor oxygenation, necrosis, and hypoxia. Overall, these findings identify EGFR mutations as key regulators of the glioma-to-pericyte transdifferentiation, highlighting the intricate relationship between the tumor cells and their vascular and immune milieu. Our results lay the foundations for a vascular-dependent stratification of gliomas and suggest different therapeutic vulnerabilities determined by the genetic status of EGFR.spa
dc.language.isoengspa
dc.publisherCancer Researchspa
dc.rightsAtribución-NoComercial-SinDerivadas 3.0 España*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/es/*
dc.subjectGliomaspa
dc.subjectPericytesspa
dc.subjectBlood-brain barrierspa
dc.subjectTumor-microenvironmentspa
dc.subjectImmune infiltratespa
dc.titleTumor-Derived Pericytes Driven by EGFR Mutations Govern the Vascular and Immune Microenvironment of Gliomas.spa
dc.typearticlespa
dc.description.versionpre-printspa
dc.rights.accessRightsopenAccessspa
dc.description.extent4836 KBspa
dc.identifier.doi10.1158/0008-5472.CAN-20-3558spa
dc.relation.publisherversionhttps://cancerres.aacrjournals.org/content/81/8/2142spa


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Except where otherwise noted, this item's license is described as Atribución-NoComercial-SinDerivadas 3.0 España