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Therapeutic targeting of the PLK1-PRC1-axis triggers cell death in genomically silent childhood cancer
Nature Communications ( IF 14.7 ) Pub Date : 2021-09-16 , DOI: 10.1038/s41467-021-25553-z
Jing Li 1, 2, 3 , Shunya Ohmura 1, 2, 3 , Aruna Marchetto 1 , Martin F Orth 1 , Roland Imle 3, 4, 5, 6 , Marlene Dallmayer 1, 7 , Julian Musa 1, 2, 3, 8 , Maximilian M L Knott 1 , Tilman L B Hölting 1 , Stefanie Stein 1 , Cornelius M Funk 1, 2, 3 , Ana Sastre 9 , Javier Alonso 10, 11 , Felix Bestvater 12 , Merve Kasan 1 , Laura Romero-Pérez 1, 2, 3 , Wolfgang Hartmann 13 , Andreas Ranft 14, 15 , Ana Banito 3, 4 , Uta Dirksen 14, 15 , Thomas Kirchner 1, 16 , Florencia Cidre-Aranaz 1, 2, 3 , Thomas G P Grünewald 1, 2, 3, 17
Affiliation  

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.



中文翻译:


PLK1-PRC1轴的治疗靶向可触发基因组沉默儿童癌症的细胞死亡



染色体不稳定 (CIN) 是癌症的一个标志1 。然而,许多儿童癌症,例如尤文肉瘤 (EwS),具有显着的“沉默”基因组,且 CIN 2极少。在这里,我们在 EwS 模型中展示了如何通过靶向胞质分裂蛋白调节蛋白 1 (PRC1) 或其激活的 polo 样激酶 1 (PLK1) 解偶联有丝分裂和胞质分裂,从而诱导致命的基因组不稳定性和肿瘤消退。我们发现 EwS 特异性致癌转录因子 EWSR1-FLI1 通过与近端增强子样 GGAA 微卫星结合来劫持PRC1 ,从而在生理上保护受控的细胞分裂,从而促进肿瘤生长和不良的临床结果。通过转录组分析和功能性体外和体内实验(包括 CRISPR 介导的增强子编辑)的整合,我们发现 PRC1 的高表达对 PLK1 抑制产生了治疗脆弱性,PLK1 抑制甚至可以通过触发有丝分裂灾难来抑制化疗耐药的 EwS 细胞。


总的来说,我们的结果证明了显性癌基因对PRC1 的异常激活如何导致恶性肿瘤,但为靶向治疗提供了机会,并确定 PRC1 表达是预测临床试验中使用的 PLK1 抑制剂疗效的重要决定因素。

更新日期:2021-09-16
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