Biology of centrosomes and genetic instability, Institut Curie, PSL Research University, CNRS UMR 144, Paris, France.
Department of Translational Research, Institut Curie, PSL University, Paris, France.
PLoS Biol. 2024 Sep 5;22(9):e3002759. doi: 10.1371/journal.pbio.3002759. eCollection 2024 Sep.
Centrosome amplification is a feature of cancer cells associated with chromosome instability and invasiveness. Enhancing chromosome instability and subsequent cancer cell death via centrosome unclustering and multipolar divisions is an aimed-for therapeutic approach. Here, we show that centrosome amplification potentiates responses to conventional chemotherapy in addition to its effect on multipolar divisions and chromosome instability. We perform single-cell live imaging of chemotherapy responses in epithelial ovarian cancer cell lines and observe increased cell death when centrosome amplification is induced. By correlating cell fate with mitotic behaviors, we show that enhanced cell death can occur independently of chromosome instability. We identify that cells with centrosome amplification are primed for apoptosis. We show they are dependent on the apoptotic inhibitor BCL-XL and that this is not a consequence of mitotic stresses associated with centrosome amplification. Given the multiple mechanisms that promote chemotherapy responses in cells with centrosome amplification, we assess such a relationship in an epithelial ovarian cancer patient cohort. We show that high centrosome numbers associate with improved treatment responses and longer overall survival. Our work identifies apoptotic priming as a clinically relevant consequence of centrosome amplification, expanding our understanding of this pleiotropic cancer cell feature.
中心体扩增是与染色体不稳定性和侵袭性相关的癌细胞特征。通过中心体解聚和多极分裂来增强染色体不稳定性并随后诱导癌细胞死亡是一种靶向治疗方法。在这里，我们表明中心体扩增除了对多极分裂和染色体不稳定性有影响外，还能增强对常规化疗的反应。我们对上皮性卵巢癌细胞系中的化疗反应进行了单细胞实时成像，并观察到中心体扩增诱导时细胞死亡增加。通过将细胞命运与有丝分裂行为相关联，我们表明增强的细胞死亡可以独立于染色体不稳定性发生。我们发现具有中心体扩增的细胞为细胞凋亡做好了准备。我们表明它们依赖于凋亡抑制剂 BCL-XL，并且这不是与中心体扩增相关的有丝分裂应激的后果。鉴于中心体扩增的细胞中存在多种促进化疗反应的机制，我们在上皮性卵巢癌患者队列中评估了这种关系。我们表明，高中心体数量与改善的治疗反应和更长的总生存期相关。我们的工作确定了凋亡引发是中心体扩增的一个临床相关后果，扩展了我们对这种多效性癌细胞特征的理解。
