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dc.contributor.authorLi, Jing
dc.contributor.authorOhmura, Shunya
dc.contributor.authorMarchetto, Aruna
dc.contributor.authorOrth, Martin F
dc.contributor.authorImle, Roland
dc.contributor.authorDallmayer, Marlene
dc.contributor.authorMusa, Julian
dc.contributor.authorKnott, Maximilian M L
dc.contributor.authorHölting, Tilman L B
dc.contributor.authorStein, Stefanie
dc.contributor.authorFunk, Cornelius M
dc.contributor.authorSastre, Ana
dc.contributor.authorAlonso, Javier 
dc.contributor.authorBestvater, Felix
dc.contributor.authorKasan, Merve
dc.contributor.authorRomero-Pérez, Laura
dc.contributor.authorHartmann, Wolfgang
dc.contributor.authorRanft, Andreas
dc.contributor.authorBanito, Ana
dc.contributor.authorDirksen, Uta
dc.contributor.authorKirchner, Thomas
dc.contributor.authorCidre-Aranaz, Florencia
dc.contributor.authorGrünewald, Thomas G P
dc.identifier.citationNat Commun. 2021 Sep 16;12(1):5356.es_ES
dc.description.abstractChromosomal instability (CIN) is a hallmark of cancer1. Yet, many childhood cancers, such as Ewing sarcoma (EwS), feature remarkably 'silent' genomes with minimal CIN2. Here, we show in the EwS model how uncoupling of mitosis and cytokinesis via targeting protein regulator of cytokinesis 1 (PRC1) or its activating polo-like kinase 1 (PLK1) can be employed to induce fatal genomic instability and tumor regression. We find that the EwS-specific oncogenic transcription factor EWSR1-FLI1 hijacks PRC1, which physiologically safeguards controlled cell division, through binding to a proximal enhancer-like GGAA-microsatellite, thereby promoting tumor growth and poor clinical outcome. Via integration of transcriptome-profiling and functional in vitro and in vivo experiments including CRISPR-mediated enhancer editing, we discover that high PRC1 expression creates a therapeutic vulnerability toward PLK1 inhibition that can repress even chemo-resistant EwS cells by triggering mitotic catastrophe.Collectively, our results exemplify how aberrant PRC1 activation by a dominant oncogene can confer malignancy but provide opportunities for targeted therapy, and identify PRC1 expression as an important determinant to predict the efficacy of PLK1 inhibitors being used in clinical trials.es_ES
dc.description.sponsorshipThis work was mainly supported by a grant from the German Cancer Aid (DKH-70114111). In addition, the laboratory of T.G.P.G. was supported by the LMU Munich’s Institutional Strategy LMUexcellent within the framework of the German Excellence Initiative, the ‘Mehr LEBEN für krebskranke Kinder—Bettina-Bräu-Stiftung’, the Matthias-Lackas Foundation, the Dr. Leopold and Carmen Ellinger Foundation, the Boehringer-Ingelheim Foundation, the Wilhelm Sander-Foundation (2016.167.1), the Barbara and Hubertus Trettner Foundation, the Dr. Rolf M. Schwiete Foundation, the Friedrich-Baur Foundation, the German Cancer Aid (DKH-70112257 and DKH-111886), the Gert und Susanna Mayer Foundation, the Barbara und Wilfried Mohr Foundation, the SMARCB1 association, and the Deutsche Forschungsgemeinschaft (DFG-391665916). J.L. was supported by a scholarship of the Chinese Scholarship Council (CSC), and a grant of the German Cancer Aid (DKH-70114111). M.D. was by a scholarship of the ‘Deutsche Stiftung für junge Erwachsene mit Krebs‘, J.M. by a scholarship of the Kind-Philipp-Foundation, and C.M.F., M.K. and T.L.B.H. by scholarships from the German Cancer Aid. The laboratory of J.A. was supported by grants from the Instituto de Salud Carlos III (PI16CIII/00026; DTS18CIII/00005), Asociación Pablo Ugarte, ASION, Fundación Sonrisa de Alex, Asociación Todos somos Iván y Asociación Candela Riera. Freely available clipart used for design of parts of figures was kindly provided by Servier Medical Art (
dc.publisherNature Publishing Group es_ES
dc.titleTherapeutic targeting of the PLK1-PRC1-axis triggers cell death in genomically silent childhood canceres_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.contributor.funderDeutsche Krebshilfe
dc.contributor.funderGerman Cancer Aid
dc.identifier.journalNature Communicationses_ES
dc.repisalud.centroISCIII::Instituto de Investigación de Enfermedades Rarases_ES
dc.rights.accessRightsopen accesses_ES

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