我们知道，正常细胞基因出现不可逆转的错误时，通常细胞会启动自我凋亡程序。而癌细胞则会携带这些突变继续生存。随着时间累积，更多的基因突变会促使癌细胞持续分裂、扩散，并对治疗药物产生耐药性。
来自于弗朗西斯•克里克研究所教授CharlesSwanton团队发现，一旦基因突变过多，同样会导致癌细胞死亡。他带领团队解析了癌细胞应对染色体异常继续生存的两种机制，相关研究成果于同一天分别发表在《Cancer Cell》和《Cancer Discovery》期刊。
《Cancer Cell》：BCL9L基因失活，促进癌细胞生存
BCL9LDysfunction Impairs Caspase-2 Expression Permitting Aneuploidy Tolerance inColorectal Cancer
染色体不稳定性（CIN）有助于癌症异质化，导致耐药性问题产生，包括染色体数目、结构异常，例如数目减少、片段缺失、易位等等。Swanton团队以直肠癌细胞系为样本发现，染色体数量异常的肠癌细胞，其BCL9L基因发生突变的概率较高。
他们证实，当染色体数目出现异常，正常细胞的BCL9L基因会激活caspase-2蛋白质，进一步启动细胞凋亡程序。但是，一旦BCL9L基因失活，染色体数量即便异常，细胞也不会表达caspase-2蛋白，反而会继续生长。这意味着，BCL9L基因突变会促进肠癌细胞在染色体数目异常的情况下继续分裂和扩散。
《Cancer Discovery》：基因紊乱超出“底线”，癌细胞也会死亡
APC/CDysfunction Limits Excessive Cancer Chromosomal Instability
虽然癌细胞能够在一定异常情况下继续生长，但是有一个“临界点”。一旦染色体不稳定性或者基因突变过多，癌细胞也会死亡。那么，癌细胞如何避免触及“底线”呢？Swanton团队进行了相关研究。
他们发现，癌细胞内存在一种机制APC/C，它出错后会让癌细胞减缓细胞分裂的进程，从而使其染色体避免发生过多错误。这一机制有助于肿瘤建立遗传多样性。当研究人员利用CRIPSR技术将APC/C机制恢复正常，癌细胞会“全速”分裂。这一改变无疑增加了染色体不稳定性，最终驱动癌细胞死亡。
CharlesSwanton教授表示：“基因组的异常导致了癌症的发生和发展，癌症异质性会影响药物治疗效果以及耐药性问题。如果癌细胞能够应对大规模基因突变，那么它将持续生长、分裂和扩散。迄今为止，我们对于癌细胞持续分裂和扩散的机制知之甚少，从而限制了我们对抗癌症的能力。这两篇研究发现有助于我们解析癌细胞分裂背后的机制。”
APC/C Dysfunction Limits Excessive CancerChromosomal Instability
DOI: 10.1158/2159-8290.CD-16-0645
Intercellularheterogeneity, exacerbated by chromosomal instability (CIN), fosters tumorheterogeneity and drug resistance. However, extreme CIN correlates withimproved cancer outcome, suggesting that karyotypic diversity required to adaptto selection pressures might be balanced in tumors against the risk ofexcessive instability. Here, we used a functional genomics screen, genomeediting, and pharmacologic approaches to identify CIN-survival factors indiploid cells. We find partial anaphase-promoting complex/cyclosome (APC/C)dysfunction lengthens mitosis, suppresses pharmacologically induced chromosomesegregation errors, and reduces naturally occurring lagging chromosomes incancer cell lines or following tetraploidization. APC/C impairment caused adaptationto MPS1 inhibitors, revealing a likely resistance mechanism to therapiestargeting the spindle assembly checkpoint. Finally, CRISPR-mediatedintroduction of cancer somatic mutations in the APC/C subunit cancer drivergene CDC27 reduces chromosome segregation errors, whereas reversal of an APC/Csubunit nonsense mutation increases CIN. Subtle variations in mitotic duration,determined by APC/C activity, influence the extent of CIN, allowing cancercells to dynamically optimize fitness during tumor evolution.
BCL9L Dysfunction Impairs Caspase-2Expression Permitting Aneuploidy Tolerance in Colorectal Cancer
DOI:http://dx.doi.org/10.1016/j.ccell.2016.11.001
Chromosomalinstability (CIN) contributes to cancer evolution, intratumor heterogeneity,and drug resistance. CIN is driven by chromosome segregation errors and atolerance phenotype that permits the propagation of aneuploid genomes. Throughgenomic analysis of colorectal cancers and cell lines, we find frequent loss ofheterozygosity and mutations in BCL9L in aneuploid tumors. BCL9L deficiencypromoted tolerance of chromosome missegregation events, propagation ofaneuploidy, and genetic heterogeneity in xenograft models likely throughmodulation of Wnt signaling. We find that BCL9L dysfunction contributes toaneuploidy tolerance in both TP53-WT and mutant cells by reducing basalcaspase-2 levels and preventing cleavage of MDM2 and BID. Efforts to exploitaneuploidy tolerance mechanisms and the BCL9L/caspase-2/BID axis may limitcancer diversity and evolution.
来源：生物探索
