Ludwig Cancer Research, Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093, USA.
European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands.
Genes Dev. 2021 Aug 1;35(15-16):1093-1108. doi: 10.1101/gad.348319.121. Epub 2021 Jul 15.
Abnormal numerical and structural chromosome content is frequently found in human cancer. To test the role of aneuploidy in tumor initiation and progression, we generated mice with random aneuploidies by transient induction of polo-like kinase 4 (Plk4), a master regulator of centrosome number. Short-term chromosome instability (CIN) from transient Plk4 induction resulted in formation of aggressive T-cell lymphomas in mice with heterozygous inactivation of one allele and accelerated tumor development in the absence of p53. Transient CIN increased the frequency of lymphoma-initiating cells with a specific karyotype profile, including trisomy of chromosomes 4, 5, 14, and 15 occurring early in tumorigenesis. Tumor development in mice with chronic CIN induced by an independent mechanism (through inactivation of the spindle assembly checkpoint) gradually trended toward a similar karyotypic profile, as determined by single-cell whole-genome DNA sequencing. Overall, we show how transient CIN generates cells with random aneuploidies from which ones that acquire a karyotype with specific chromosome gains are sufficient to drive cancer formation, and that distinct CIN mechanisms can lead to similar karyotypic cancer-causing outcomes.
人类癌症中经常发现异常的数字和结构染色体含量。为了测试非整倍体在肿瘤发生和进展中的作用，我们通过短暂诱导中心体数量的主要调节因子 Polo 样激酶 4（Plk4），产生了具有随机非整倍体的小鼠。短期染色体不稳定性（CIN）来自短暂的 Plk4 诱导，导致杂合性失活一个等位基因的小鼠形成侵袭性 T 细胞淋巴瘤，并在没有 p53 的情况下加速肿瘤发展。短暂的 CIN 增加了具有特定核型特征的淋巴瘤起始细胞的频率，包括在肿瘤发生早期发生的染色体 4、5、14 和 15 的三体。通过独立机制（通过失活纺锤体组装检查点）诱导的慢性 CIN 中的肿瘤发展逐渐趋于类似的核型特征，这是通过单细胞全基因组 DNA 测序确定的。总的来说，我们展示了短暂的 CIN 如何从具有随机非整倍体的细胞中产生，其中获得具有特定染色体增益的核型足以驱动癌症形成，并且不同的 CIN 机制可以导致相似的核型致癌结果。
