小柯机器人

美国哈佛医学院Aviv Regev、Joan S. Brugge等研究人员合作发现，循环肿瘤持久者细胞产生于具有不同程序的谱系。该研究于2021年8月11日在线发表于国际一流学术期刊《自然》。

研究人员表示，最近出现的非遗传机制是癌症治疗失败的重要驱动因素，一些癌细胞在治疗过程中可以进入可逆的耐药宿主状态。虽然大多数癌症宿主在药物存在的情况下仍然处于停滞状态，但在构成性药物治疗下，一个罕见的亚群可以重新进入细胞周期。人们对使癌症宿主在药物存在下保持增殖能力的非遗传机制知之甚少。

为了研究这种罕见的、瞬时抗性的增殖性的宿主群体，研究人员开发了Watermelon，一种高复杂度的表达型条形码慢病毒库，用于同时追踪每个细胞的克隆来源以及增殖和转录状态。结果表明，循环和非循环的持久者产生于不同的细胞系，并具有不同的转录和代谢程序。抗氧化基因程序的上调和向脂肪酸氧化的代谢转变与多种癌症类型的持久性增殖能力有关。阻碍氧化应激或代谢重编程改变了循环持久者的比例。

在人类肿瘤中，与循环性持久者有关的程序在对多种靶向治疗的反应中诱发了最小的残留疾病。Watermelon系统能够识别出罕见的持久性细胞系，这些细胞系在药物压力下会优先增殖，从而暴露出新的弱点，可以作为延缓甚至防止疾病复发的靶标。

附：英文原文

Title: Cycling cancer persister cells arise from lineages with distinct programs

Author: Oren, Yaara, Tsabar, Michael, Cuoco, Michael S., Amir-Zilberstein, Liat, Cabanos, Heidie F., Htter, Jan-Christian, Hu, Bomiao, Thakore, Pratiksha I., Tabaka, Marcin, Fulco, Charles P., Colgan, William, Cuevas, Brandon M., Hurvitz, Sara A., Slamon, Dennis J., Deik, Amy, Pierce, Kerry A., Clish, Clary, Hata, Aaron N., Zaganjor, Elma, Lahav, Galit, Politi, Katerina, Brugge, Joan S., Regev, Aviv

Issue&Volume: 2021-08-11

Abstract: 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.

DOI: 10.1038/s41586-021-03796-6

Source: https://www.nature.com/articles/s41586-021-03796-6

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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