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dc.contributor.authorKuciak, Monika
dc.contributor.authorMas, Christophe
dc.contributor.authorBorges, Isabel
dc.contributor.authorSanchez-Gomez, Pilar 
dc.contributor.authorRuiz i Altaba, Ariel
dc.identifier.citationSci Rep. 2019 Mar 7;9(1):3891es_ES
dc.description.abstractTargeting stemness promises new therapeutic strategies against highly invasive tumors. While a number of approaches are being tested, inhibiting the core transcription regulatory network of cancer stem cells is an attractive yet challenging possibility. Here we have aimed to provide the proof of principle for a strategy, previously used in developmental studies, to directly repress the targets of a salient stemness and pluripotency factor: NANOG. In doing so we expected to inhibit the expression of so far unknown mediators of pro-tumorigenic NANOG function. We chose NANOG since previous work showed the essential requirement for NANOG activity for human glioblastoma (GBM) growth in orthotopic xenografts, and it is apparently absent from many adult human tissues thus likely minimizing unwanted effects on normal cells. NANOG repressor chimeras, which we name NANEPs, bear the DNA-binding specificity of NANOG through its homeodomain (HD), and this is linked to transposable human repressor domains. We show that in vitro and in vivo, NANEP5, our most active NANEP with a HES1 repressor domain, mimics knock-down (kd) of NANOG function in GBM cells. Competition orthotopic xenografts also reveal the effectiveness of NANEP5 in a brain tumor context, as well as the specificity of NANEP activity through the abrogation of its function via the introduction of specific mutations in the HD. The transcriptomes of cells expressing NANEP5 reveal multiple potential mediators of pro-tumorigenic NANEP/NANOG action including intercellular signaling components. The present results encourage further studies on the regulation of context-dependent NANEP abundance and function, and the development of NANEP-based anti-cancer therapies.es_ES
dc.description.sponsorshipThis work was supported by a James McDonnell Brain Cancer Award, Fondation Eclosion funds and by the Département d’Instruction Publique de Genève to ARA. C.M. and M.K. were fellows of the ITN-EU networks CAPPELLA and HEALING, respectively.es_ES
dc.publisherSpringer Naturees_ES
dc.relation.isversionofPublisher's versiones_ES
dc.titleChimeric NANOG repressors inhibit glioblastoma growth in vivo in a context-dependent manneres_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.contributor.funderFondation Eclosion
dc.contributor.funderJames McDonnell Brain Cancer Award
dc.contributor.funderDépartement d’Instruction Publique de Genève
dc.identifier.journalScientific Reportses_ES
dc.repisalud.centroISCIII::Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC)es_ES

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Atribución 4.0 Internacional
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