多药耐受
生物
癌细胞
转录组
癌症
人口
重编程
基因
癌症研究
遗传学
医学
基因表达
生物膜
细菌
环境卫生
作者
Yaara Oren,Michael Tsabar,Michael S. Cuoco,Liat Amir-Zilberstein,Heidie Frisco Cabanos,Jan-Christian Hütter,Bomiao Hu,Pratiksha I. Thakore,Marcin Tabaka,Charles P. Fulco,William Colgan,Brandon M. Cuevas,Sara A. Hurvitz,Dennis J. Slamon,Amy Deik,Kerry A. Pierce,Clary B. Clish,Aaron N. Hata,Elma Zaganjor,Galit Lahav,Katerina Politi,Joan S. Brugge,Aviv Regev
出处
期刊:Nature
[Springer Nature]
日期:2021-08-11
卷期号:596 (7873): 576-582
被引量:230
标识
DOI:10.1038/s41586-021-03796-6
摘要
Non-genetic mechanisms have recently emerged as important drivers of cancer therapy failure1, where some cancer cells can enter a reversible drug-tolerant persister state in response to treatment2. Although most cancer persisters remain arrested in the presence of the drug, a rare subset can re-enter the cell cycle under constitutive drug treatment. Little is known about the non-genetic mechanisms that enable cancer persisters to maintain proliferative capacity in the presence of drugs. To study this rare, transiently resistant, proliferative persister population, we developed Watermelon, a high-complexity expressed barcode lentiviral library for simultaneous tracing of each cell's clonal origin and proliferative and transcriptional states. Here we show that cycling and non-cycling persisters arise from different cell lineages with distinct transcriptional and metabolic programs. Upregulation of antioxidant gene programs and a metabolic shift to fatty acid oxidation are associated with persister proliferative capacity across multiple cancer types. Impeding oxidative stress or metabolic reprogramming alters the fraction of cycling persisters. In human tumours, programs associated with cycling persisters are induced in minimal residual disease in response to multiple targeted therapies. The Watermelon system enabled the identification of rare persister lineages that are preferentially poised to proliferate under drug pressure, thus exposing new vulnerabilities that can be targeted to delay or even prevent disease recurrence.
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