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Artículo
Therapeutic targeting of the PLK1-PRC1-axis triggers cell death in genomically silent childhood cancer
Autor/es | Li, Jing
Ohmura, Shunya Marchetto, Aruna Orth, Martin F. Imle, Roland Dallmayer, Marlene Romero Pérez, Laura Grünewald, Thomas G. P. |
Departamento | Universidad de Sevilla. Departamento de Citología e Histología Normal y Patológica |
Fecha de publicación | 2021-09-16 |
Fecha de depósito | 2022-12-20 |
Publicado en |
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Resumen | 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 ... 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. |
Agencias financiadoras | Asociacion Pablo Ugarte Asociacion Todos somos Ivan y Asociacion Candela Riera Instituto de Salud Carlos III |
Identificador del proyecto | PI16CIII/00026
DTS18CIII/00005 DFG-391665916 DKH-70114111 DKH-70112257 DKH-111886 2016.167.1 |
Cita | Li, J., Ohmura, S., Marchetto, A., Orth, M.F., Imle, R., Dallmayer, M.,...,Grünewald, T.G.P. (2021). Therapeutic targeting of the PLK1-PRC1-axis triggers cell death in genomically silent childhood cancer. Nature Communications, 12 (1), 5356. https://doi.org/10.1038/s41467-021-25553-z. |
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