2026-04-30T03:51:08Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/134272025-06-17T09:53:18Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19616
Repisalud
author
Li, Jing
author
Ohmura, Shunya
author
Marchetto, Aruna
author
Orth, Martin F
author
Imle, Roland
author
Dallmayer, Marlene
author
Musa, Julian
author
Knott, Maximilian M L
author
Hölting, Tilman L B
author
Stein, Stefanie
author
Funk, Cornelius M
author
Sastre, Ana
author
Alonso, Javier
author
Bestvater, Felix
author
Kasan, Merve
author
Romero-Pérez, Laura
author
Hartmann, Wolfgang
author
Ranft, Andreas
author
Banito, Ana
author
Dirksen, Uta
author
Kirchner, Thomas
author
Cidre-Aranaz, Florencia
author
Grünewald, Thomas G P
funder
Deutsche Krebshilfe
funder
German Cancer Aid
2021-10-08T11:52:41Z
2021-10-08T11:52:41Z
2021-09-16
Nat Commun. 2021 Sep 16;12(1):5356.
10.1038/s41467-021-25553-z
2041-1723
Nature Communications
34531368
http://hdl.handle.net/20.500.12105/13427
Chromosomal 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.
eng
Therapeutic targeting of the PLK1-PRC1-axis triggers cell death in genomically silent childhood cancer
research article
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