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Cycling cancer persister cells arise from lineages with distinct programs

机译：循环癌症泄漏细胞出现来自具有不同计划的谱系

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摘要

Non-genetic mechanisms have recently emerged as important drivers of cancer therapy failure(1), where some cancer cells can enter a reversible drug-tolerant persister state in response to treatment(2). 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.
机译：最近出现了非遗传机制作为癌症治疗衰竭（1）的重要司机，其中一些癌细胞可以响应于治疗而进入可逆的耐受耐受抗抗体状态（2）。虽然大多数癌症持续体在药物存在下仍然被捕，但是罕见的子集可以根据本构类药物治疗重新进入细胞周期。关于非遗传机制的众所周知，使癌症持续存在在药物存在下保持增殖能力。为了研究这种罕见，致力的致力致力，耐高采烈的抗体，我们开发了西瓜，一种高复杂性表达的条形码慢病毒文库，用于同时描绘各种细胞的克隆来源和增殖和转录状态。在这里，我们表明骑自行车和非循环滞后来自不同的细胞谱系，具有不同的转录和代谢程序。抗氧化基因计划的上调和对脂肪酸氧化的代谢转变与患有多种癌症类型的抗病性能力相关。阻碍氧化应激或代谢重编程改变了循环滞留的一部分。在人肿瘤中，响应于多个靶向疗法，在最小的残留疾病中诱导与循环滞后相关的程序。西瓜系统使识别优先考虑在药物压力下促进的稀有抗锯齿谱系，从而暴露出可以针对延迟甚至预防疾病复发的新脆弱性。

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  • 来源
    《Nature》 |2021年第7873期|576-582|共7页
  • 作者

    Oren Yaara; Tsabar Michael; Cuoco Michael S.; Amir-Zilberstein Liat; Cabanos Heidie F.; Hutter 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;

  • 作者单位

    Broad Inst MIT & Harvard Klarman Cell Observ Cambridge MA 02142 USA|Harvard Med Sch Dept Cell Biol Boston MA 02115 USA;

    Broad Inst MIT & Harvard Klarman Cell Observ Cambridge MA 02142 USA|Harvard Med Sch Dept Syst Biol Boston MA 02115 USA|Harvard Med Sch Lab Syst Pharmacol Boston MA 02115 USA;

    Broad Inst MIT & Harvard Klarman Cell Observ Cambridge MA 02142 USA;

    Broad Inst MIT & Harvard Klarman Cell Observ Cambridge MA 02142 USA;

    Massachusetts Gen Hosp Dept Med Boston MA 02114 USA|Harvard Med Sch Dept Med Boston MA 02115 USA;

    Broad Inst MIT & Harvard Klarman Cell Observ Cambridge MA 02142 USA;

    Yale Sch Med Dept Pathol New Haven CT USA;

    Broad Inst MIT & Harvard Klarman Cell Observ Cambridge MA 02142 USA;

    Broad Inst MIT & Harvard Klarman Cell Observ Cambridge MA 02142 USA;

    Broad Inst MIT & Harvard Cambridge MA 02142 USA|Bristol Myers Squibb Cambridge MA USA;

    Broad Inst MIT & Harvard Cambridge MA 02142 USA;

    Broad Inst MIT & Harvard Klarman Cell Observ Cambridge MA 02142 USA;

    Univ Calif Los Angeles David Geffen Sch Med Los Angeles CA 90095 USA|Jonsson Comprehens Canc Ctr Los Angeles CA 90034 USA;

    Univ Calif Los Angeles David Geffen Sch Med Los Angeles CA 90095 USA|Jonsson Comprehens Canc Ctr Los Angeles CA 90034 USA;

    Broad Inst Metabol Platform Cambridge MA USA;

    Broad Inst Metabol Platform Cambridge MA USA;

    Broad Inst Metabol Platform Cambridge MA USA;

    Massachusetts Gen Hosp Dept Med Boston MA 02114 USA|Harvard Med Sch Dept Med Boston MA 02115 USA;

    Vanderbilt Univ Dept Mol Physiol & Biophys Nashville TN 37232 USA;

    Yale Sch Med Dept Pathol Sect Med Oncol New Haven CT USA|Yale Canc Ctr New Haven CT USA;

    Harvard Med Sch Dept Cell Biol Boston MA 02115 USA|Ludwig Ctr Harvard Boston MA 02215 USA;

    Broad Inst MIT & Harvard Klarman Cell Observ Cambridge MA 02142 USA|MIT Dept Biol Cambridge MA 02139 USA|Howard Hughes Med Inst Chevy Chase MD 20815 USA|Genentech Inc San Francisco CA 94080 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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