小柯机器人

以色列特拉维夫大学Uri Ben-David团队发现，非整倍性使癌细胞对有丝分裂检查点更为敏感。相关论文于2021年1月27日在线发表于国际学术期刊《自然》。

研究人员绘制了约1,000种人类癌细胞系的非整倍性图谱，并分析了遗传和化学扰动筛选，以确定与非整倍性相关的细胞靶点。研究人员发现非整倍体癌细胞对纺锤体装配检查点（SAC）核心组件的遗传扰动表现出更高的敏感性，从而确保有丝分裂期间染色体的正确分离。出乎意料的是，研究人员还发现非整倍体癌细胞对短期暴露于多种SAC抑制剂的敏感性低于二倍体癌细胞。

实际上，随着时间的推移，非整倍体癌细胞对SAC抑制作用变得越来越敏感。非整倍体细胞表现出异常的纺锤体几何形状和动力学，并在抑制SAC时保持分裂，导致有丝分裂缺陷的积累，并形成不稳定且不太适合的核型。因此，尽管非整倍体癌细胞比二倍体细胞更容易克服SAC抑制作用，但它们的长期增殖受到威胁。

研究人员确定了一种特定的有丝分裂驱动蛋白，KIF18A，其活性在非整倍性癌细胞中受到干扰。非整倍体癌细胞特别容易耗尽KIF18A，并且KIF18A过表达恢复了它们对SAC抑制的反应。这些结果确定了非整倍性与SAC之间在治疗上相关的合成致死相互作用。 

据悉，非整倍体细胞的选择性靶向是一种潜在的癌症治疗策略。然而，目前尚不清楚非整倍性是否会在癌细胞中产生任何临床相关的治疗靶点。

附：英文原文

Title: Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition

Author: Yael Cohen-Sharir, James M. McFarland, Mai Abdusamad, Carolyn Marquis, Sara V. Bernhard, Mariya Kazachkova, Helen Tang, Marica R. Ippolito, Kathrin Laue, Johanna Zerbib, Heidi L. H. Malaby, Andrew Jones, Lisa-Marie Stautmeister, Irena Bockaj, Ren Wardenaar, Nicholas Lyons, Ankur Nagaraja, Adam J. Bass, Diana C. J. Spierings, Floris Foijer, Rameen Beroukhim, Stefano Santaguida, Todd R. Golub, Jason Stumpff, Zuzana Storchov, Uri Ben-David

Issue&Volume: 2021-01-27

Abstract: Selective targeting of aneuploid cells is an attractive strategy for cancer treatment1. However, it is unclear whether aneuploidy generates any clinically relevant vulnerabilities in cancer cells. Here we mapped the aneuploidy landscapes of about 1,000 human cancer cell lines, and analysed genetic and chemical perturbation screens2,3,4,5,6,7,8,9 to identify cellular vulnerabilities associated with aneuploidy. We found that aneuploid cancer cells show increased sensitivity to genetic perturbation of core components of the spindle assembly checkpoint (SAC), which ensures the proper segregation of chromosomes during mitosis10. Unexpectedly, we also found that aneuploid cancer cells were less sensitive than diploid cells to short-term exposure to multiple SAC inhibitors. Indeed, aneuploid cancer cells became increasingly sensitive to inhibition of SAC over time. Aneuploid cells exhibited aberrant spindle geometry and dynamics, and kept dividing when the SAC was inhibited, resulting in the accumulation of mitotic defects, and in unstable and less-fit karyotypes. Therefore, although aneuploid cancer cells could overcome inhibition of SAC more readily than diploid cells, their long-term proliferation was jeopardized. We identified a specific mitotic kinesin, KIF18A, whose activity was perturbed in aneuploid cancer cells. Aneuploid cancer cells were particularly vulnerable to depletion of KIF18A, and KIF18A overexpression restored their response to SAC inhibition. Our results identify a therapeutically relevant, synthetic lethal interaction between aneuploidy and the SAC.

DOI: 10.1038/s41586-020-03114-6

Source: https://www.nature.com/articles/s41586-020-03114-6

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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