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Chromosomal instability accelerates the evolution of resistance to anti-cancer therapies
Developmental Cell ( IF 10.7 ) Pub Date : 2021-08-04 , DOI: 10.1016/j.devcel.2021.07.009
Devon A Lukow 1 , Erin L Sausville 2 , Pavit Suri 2 , Narendra Kumar Chunduri 3 , Angela Wieland 4 , Justin Leu 2 , Joan C Smith 5 , Vishruth Girish 2 , Ankith A Kumar 6 , Jude Kendall 2 , Zihua Wang 2 , Zuzana Storchova 4 , Jason M Sheltzer 2
Affiliation  

Aneuploidy is a ubiquitous feature of human tumors, but the acquisition of aneuploidy typically antagonizes cellular fitness. To investigate how aneuploidy could contribute to tumor growth, we triggered periods of chromosomal instability (CIN) in human cells and then exposed them to different culture environments. We discovered that transient CIN reproducibly accelerates the acquisition of resistance to anti-cancer therapies. Single-cell sequencing revealed that these resistant populations develop recurrent aneuploidies, and independently deriving one chromosome-loss event that was frequently observed in paclitaxel-resistant cells was sufficient to decrease paclitaxel sensitivity. Finally, we demonstrated that intrinsic levels of CIN correlate with poor responses to numerous therapies in human tumors. Our results show that, although CIN generally decreases cancer cell fitness, it also provides phenotypic plasticity to cancer cells that can allow them to adapt to diverse stressful environments. Moreover, our findings suggest that aneuploidy may function as an under-explored cause of therapy failure.



中文翻译:


染色体不稳定性加速抗癌疗法耐药性的进化



非整倍性是人类肿瘤的普遍特征,但非整倍性的获得通常会拮抗细胞适应性。为了研究非整倍性如何促进肿瘤生长,我们触发了人类细胞的染色体不稳定期(CIN),然后将它们暴露于不同的培养环境中。我们发现短暂的 CIN 可重复地加速抗癌治疗耐药性的获得。单细胞测序显示,这些耐药群体会反复出现非整倍体,并且独立地衍生出在紫杉醇耐药细胞中经常观察到的一种染色体丢失事件,足以降低紫杉醇的敏感性。最后,我们证明了 CIN 的内在水平与人类肿瘤中多种疗法的不良反应相关。我们的结果表明,虽然 CIN 通常会降低癌细胞的适应性,但它​​也为癌细胞提供了表型可塑性,使它们能够适应不同的压力环境。此外,我们的研究结果表明,非整倍体可能是治疗失败的一个尚未充分探索的原因。

更新日期:2021-09-13
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