Transient genomic instability drives tumorigenesis through accelerated clonal evolution.
Transient genomic instability drives tumorigenesis through accelerated clonal evolution.
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DOI：
10.1101/gad.348319.121
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发表时间：
2021-08-01
影响因子：
10.5
通讯作者：
Cleveland DW
中科院分区：
文献类型：
--
作者：
Shoshani O;Bakker B;de Haan L;Tijhuis AE;Wang Y;Kim DH;Maldonado M;Demarest MA;Artates J;Zhengyu O;Mark A;Wardenaar R;Sasik R;Spierings DCJ;Vitre B;Fisch K;Foijer F;Cleveland DW
在这项研究中，Shoshani等人测试了非整倍性在肿瘤发生和进展中的作用，并通过瞬时诱导polo样激酶4（Plk 4）（中心体数量的主要调节因子）产生随机非整倍性小鼠。他们的研究结果表明，瞬时CIN如何产生具有随机非整倍性的细胞，从中获得具有特定染色体增益的核型的细胞足以驱动癌症形成，并且不同的CIN机制可以导致类似的核型致癌结果。异常的染色体数目和结构含量经常在人类癌症中发现。为了测试非整倍体在肿瘤发生和发展中的作用，我们通过瞬时诱导polo样激酶4（Plk 4）（一种中心体数量的主要调节因子）产生随机非整倍体小鼠。短暂Plk4诱导的短期染色体不稳定性（CIN）导致一个p53等位基因杂合失活的小鼠形成侵袭性T细胞淋巴瘤，并在p53缺失的情况下加速肿瘤发展。一过性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4、5、14和15号染色体三体。通过单细胞全基因组DNA测序确定，由独立机制（通过纺锤体组装检查点失活）诱导的慢性CIN小鼠的肿瘤发展逐渐趋向于相似的核型特征。总的来说，我们展示了瞬时CIN如何产生具有随机非整倍性的细胞，从中获得具有特定染色体增益的核型的细胞足以驱动癌症形成，并且不同的CIN机制可以导致类似的核型致癌结果。
In this study, Shoshani et al. tested the role of aneuploidy in tumor initiation and progression, and generated mice with random aneuploidies by transient induction of polo-like kinase 4 (Plk4), a master regulator of centrosome number. Their findings 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. 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 p53 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.
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