Cycling cancer persister cells arise from lineages with distinct programs.
Cycling cancer persister cells arise from lineages with distinct programs.
复制标题
循环的癌症持久细胞起源于具有不同程序的谱系。
DOI：
10.1038/s41586-021-03796-6
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发表时间：
2021-08
期刊：
影响因子：
64.8
通讯作者：
中科院分区：
文献类型：
--
作者：
非遗传机制最近已成为癌症治疗失败的重要驱动因素，其中一些癌细胞可以响应于治疗而进入可逆的药物耐受持续状态。虽然大多数癌症持续者在药物存在下仍然被阻止，但在组成性药物治疗下，罕见的子集可以重新进入细胞周期。关于使癌症持续者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、增殖性的持续存在的群体，我们开发了西瓜，一种高复杂性表达的条形码慢病毒文库，用于同时追踪每个细胞的克隆起源以及增殖和转录状态。在这里，我们表明，循环和非循环的坚持者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续增殖能力相关。阻碍氧化应激或代谢重编程显着改变循环持续的分数。在人类肿瘤中，与循环持续相关的程序在响应于多种靶向治疗的微小残留病中被诱导。西瓜系统能够识别出在药物压力下优先准备增殖的罕见持久性谱系，从而暴露出可以靶向延迟甚至预防疾病复发的新漏洞。
Non-genetic mechanisms have recently emerged as important drivers of cancer therapy failure, where some cancer cells can enter a reversible drug-tolerant persister state in response to treatment. While most cancer persisters remain arrested in the presence of 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 drug. 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 significantly 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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影响因子：
50.3
作者：
Guler, Gulfem Dilek;Tindell, Charles Albert;Classon, Marie
通讯作者：
Classon, Marie
DOI：
10.1126/science.aad0501
发表时间：
2016-04-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Tirosh I;Izar B;Prakadan SM;Wadsworth MH 2nd;Treacy D;Trombetta JJ;Rotem A;Rodman C;Lian C;Murphy G;Fallahi-Sichani M;Dutton-Regester K;Lin JR;Cohen O;Shah P;Lu D;Genshaft AS;Hughes TK;Ziegler CG;Kazer SW;Gaillard A;Kolb KE;Villani AC;Johannessen CM;Andreev AY;Van Allen EM;Bertagnolli M;Sorger PK;Sullivan RJ;Flaherty KT;Frederick DT;Jané-Valbuena J;Yoon CH;Rozenblatt-Rosen O;Shalek AK;Regev A;Garraway LA
通讯作者：
Garraway LA
影响因子：
4.1
作者：
Chong, Jasmine;Yamamoto, Mai;Xia, Jianguo
通讯作者：
Xia, Jianguo
影响因子：
82.9
作者：
Hata AN;Niederst MJ;Archibald HL;Gomez-Caraballo M;Siddiqui FM;Mulvey HE;Maruvka YE;Ji F;Bhang HE;Krishnamurthy Radhakrishna V;Siravegna G;Hu H;Raoof S;Lockerman E;Kalsy A;Lee D;Keating CL;Ruddy DA;Damon LJ;Crystal AS;Costa C;Piotrowska Z;Bardelli A;Iafrate AJ;Sadreyev RI;Stegmeier F;Getz G;Sequist LV;Faber AC;Engelman JA
通讯作者：
Engelman JA
影响因子：
64.8
作者：
Shaffer SM;Dunagin MC;Torborg SR;Torre EA;Emert B;Krepler C;Beqiri M;Sproesser K;Brafford PA;Xiao M;Eggan E;Anastopoulos IN;Vargas-Garcia CA;Singh A;Nathanson KL;Herlyn M;Raj A
通讯作者：
Raj A