Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Stony Brook University, Stony Brook, NY 11794, USA.
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Dev Cell. 2021 Sep 13;56(17):2427-2439.e4. doi: 10.1016/j.devcel.2021.07.009. Epub 2021 Aug 4.
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.
非整倍体是人类肿瘤的普遍特征，但获得非整倍体通常会拮抗细胞适应性。为了研究非整倍体如何促进肿瘤生长，我们在人类细胞中引发染色体不稳定（CIN）期，然后将其暴露于不同的培养环境中。我们发现短暂的 CIN 可重复性地加速获得对癌症治疗的抗性。单细胞测序揭示了这些耐药群体反复出现非整倍体，并且在紫杉醇耐药细胞中经常观察到的独立衍生的一次染色体丢失事件足以降低紫杉醇敏感性。最后，我们证明了内在的 CIN 水平与人类肿瘤对多种治疗方法的不良反应相关。我们的研究结果表明，尽管 CIN 通常会降低癌细胞适应性，但它也为癌细胞提供了表型可塑性，使它们能够适应各种应激环境。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未被充分探索的原因。
