Diverse clonal fates emerge upon drug treatment of homogeneous cancer cells.
Diverse clonal fates emerge upon drug treatment of homogeneous cancer cells.
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在均质癌细胞的药物治疗后，出现了多种克隆命运。
DOI：
10.1038/s41586-023-06342-8
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发表时间：
2023-08
期刊：
影响因子：
64.8
通讯作者：
Raj, Arjun
中科院分区：
文献类型：
--
作者：
Goyal, Yogesh;Busch, Gianna T. T.;Pillai, Maalavika;Li, Jingxin;Boe, Ryan H. H.;Grody, Emanuelle I. I.;Chelvanambi, Manoj;Dardani, Ian P. P.;Emert, Benjamin;Bodkin, Nicholas;Braun, Jonas;Fingerman, Dylan;Kaur, Amanpreet;Jain, Naveen;Ravindran, Pavithran T. T.;Mellis, Ian A. A.;Kiani, Karun;Alicea, Gretchen M. M.;Fane, Mitchell E. E.;Ahmed, Syeda Subia;Li, Haiyin;Chen, Yeqing;Chai, Cedric;Kaster, Jessica;Witt, Russell G. G.;Lazcano, Rossana;Ingram, Davis R. R.;Johnson, Sarah B. B.;Wani, Khalida;Dunagin, Margaret C. C.;Lazar, Alexander J. J.;Weeraratna, Ashani T. T.;Wargo, Jennifer A. A.;Herlyn, Meenhard;Raj, Arjun
即使在基因相同的癌细胞中，对治疗的抵抗力也经常出现在这些细胞的一小部分中。初始群体中罕见个体细胞的分子差异使某些细胞对治疗产生耐药性;然而，对耐药性结果的变异性知之甚少。在这里，我们开发并应用FateMap，一个将DNA条形码与单细胞RNA测序相结合的框架，以揭示数十万个暴露于抗癌疗法的克隆的命运。我们发现，从单细胞来源的癌细胞中产生的耐药克隆在分子、形态和功能上都具有不同的耐药类型。这些耐药类型在很大程度上是由药物添加前细胞之间的分子差异而不是由外在因素预先确定的。药物剂量和类型的变化可以改变初始细胞的耐药类型，导致某些耐药类型的产生和消除。来自患者的样本显示了在临床背景下存在这些耐药类型的证据。我们观察到几种单细胞来源的癌细胞系和用多种药物治疗的细胞类型的耐药类型的多样性。由于内在细胞状态的可变性而导致的抗性类型的多样性可能是对外部线索的反应的一般特征。
Even among genetically identical cancer cells, resistance to therapy frequently emerges from a small subset of those cells. Molecular differences in rare individual cells in the initial population enable certain cells to become resistant to therapy; however, comparatively little is known about the variability in the resistance outcomes. Here we develop and apply FateMap, a framework that combines DNA barcoding with single-cell RNA sequencing, to reveal the fates of hundreds of thousands of clones exposed to anti-cancer therapies. We show that resistant clones emerging from single-cell-derived cancer cells adopt molecularly, morphologically and functionally distinct resistant types. These resistant types are largely predetermined by molecular differences between cells before drug addition and not by extrinsic factors. Changes in the dose and type of drug can switch the resistant type of an initial cell, resulting in the generation and elimination of certain resistant types. Samples from patients show evidence for the existence of these resistant types in a clinical context. We observed diversity in resistant types across several single-cell-derived cancer cell lines and cell types treated with a variety of drugs. The diversity of resistant types as a result of the variability in intrinsic cell states may be a generic feature of responses to external cues.
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影响因子：
28.2
作者：
Kaur A;Ecker BL;Douglass SM;Kugel CH 3rd;Webster MR;Almeida FV;Somasundaram R;Hayden J;Ban E;Ahmadzadeh H;Franco-Barraza J;Shah N;Mellis IA;Keeney F;Kossenkov A;Tang HY;Yin X;Liu Q;Xu X;Fane M;Brafford P;Herlyn M;Speicher DW;Wargo JA;Tetzlaff MT;Haydu LE;Raj A;Shenoy V;Cukierman E;Weeraratna AT
通讯作者：
Weeraratna AT
影响因子：
64.8
作者：
通讯作者：
--
在接种人诱导多能干细胞后不久就会进行心脏分化的细胞类型测定。
影响因子：
12.3
作者：
Jiang CL;Goyal Y;Jain N;Wang Q;Truitt RE;Coté AJ;Emert B;Mellis IA;Kiani K;Yang W;Jain R;Raj A
通讯作者：
Raj A
影响因子：
--
作者：
Garcia, Maxime;Juhos, Szilveszter;Nystedt, Bjorn
通讯作者：
Nystedt, Bjorn
影响因子：
51.1
作者：
Amaria, Rodabe N.;Prieto, Peter A.;Wargo, Jennifer A.
通讯作者：
Wargo, Jennifer A.