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全基因组加倍导致肿瘤细胞产生独特的遗传脆弱性
2021-01-28 14:09

2021年1月27日,美国波士顿大学医学院Neil J. Ganem研究组在《自然》杂志发表论文,宣布他们发现全基因组加倍(WGD)使得肿瘤细胞产生独特的遗传敏感性。

使用约10,000种人原发性癌症样本的测序数据和大约600种癌细胞系的必需数据,研究人员证明WGD产生了常见的遗传特征,并伴有独特的脆弱性。研究揭示了WGD+细胞比WGD-细胞更依赖于纺锤体装配检查点、DNA复制因子和蛋白酶体功能的信号传导。

研究人员还发现了KIF18A是WGD+活性细胞所特有的,KIF18A编码有丝分裂驱动蛋白。尽管KIF18A对WGD-细胞有丝分裂过程中染色体的正确分离非常重要,但其丢失会导致WGD+细胞产生明显的有丝分裂错误,最终损害细胞活力。

总的来说,该研究结果提出了一种新的治疗策略,其特异性靶向WGD+癌细胞,同时保留了包含人体组织的正常、未转化的WGD-细胞。

据悉,在人类癌症中经常发生WGD,其发生在肿瘤产生早期并导致遗传不稳定的四倍体细胞产生,加快了肿瘤的进展。经历WGD的细胞(WGD+细胞)必须适应其异常的四倍体状态。但是,尚不清楚这些适应措施的性质以及它们是否具有治疗可用性。

附:英文原文

Title: Whole-genome doubling confers unique genetic vulnerabilities on tumour cells

Author: Ryan J. Quinton, Amanda DiDomizio, Marc A. Vittoria, Kristna Kotnkov, Carlos J. Ticas, Sheena Patel, Yusuke Koga, Jasmine Vakhshoorzadeh, Nicole Hermance, Taruho S. Kuroda, Neha Parulekar, Alison M. Taylor, Amity L. Manning, Joshua D. Campbell, Neil J. Ganem

Issue&Volume: 2021-01-27

Abstract: Whole-genome doubling (WGD) is common in human cancers, occurring early in tumorigenesis and generating genetically unstable tetraploid cells that fuel tumour development1,2. Cells that undergo WGD (WGD+ cells) must adapt to accommodate their abnormal tetraploid state; however, the nature of these adaptations, and whether they confer vulnerabilities that can be exploited therapeutically, is unclear. Here, using sequencing data from roughly 10,000 primary human cancer samples and essentiality data from approximately 600 cancer cell lines, we show that WGD gives rise to common genetic traits that are accompanied by unique vulnerabilities. We reveal that WGD+ cells are more dependent than WGD cells on signalling from the spindle-assembly checkpoint, DNA-replication factors and proteasome function. We also identify KIF18A, which encodes a mitotic kinesin protein, as being specifically required for the viability of WGD+ cells. Although KIF18A is largely dispensable for accurate chromosome segregation during mitosis in WGD– cells, its loss induces notable mitotic errors in WGD+ cells, ultimately impairing cell viability. Collectively, our results suggest new strategies for specifically targeting WGD+ cancer cells while sparing the normal, non-transformed WGD cells that comprise human tissue.

DOI: 10.1038/s41586-020-03133-3

Source:https://www.nature.com/articles/s41586-020-03133-3

 

 

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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