Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance.
Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance.
复制标题
DOI：
10.1038/nature22794
复制
发表时间：
2017-06-15
期刊：
影响因子：
64.8
通讯作者：
Raj A
中科院分区：
文献类型：
--
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
针对癌症中发生突变的信号分子的治疗通常可以产生显著的短期效果，但耐药癌细胞的出现是完全治愈的主要障碍。耐药性可以由继发性突变引起，但有时没有明确的遗传原因，这增加了非遗传性罕见细胞变异性的可能性。在这里，我们表明黑色素瘤细胞可以在单细胞水平上显示出深刻的转录变异性，这可以预测哪些细胞最终会抵抗药物治疗。这种变异性包括在很小比例的细胞中高水平的一些抗性标记的罕见的半协调转录。然后，药物的加入诱导这些细胞的表观遗传重编程，将短暂的转录状态转化为稳定的耐药状态。这种重编程始于sox10介导的分化缺失，随后是新的信号通路的激活，部分由Jun-AP-1和TEAD的活性介导。我们的工作揭示了耐药获得的多阶段性质，并为理解单细胞的耐药动力学提供了一个框架。我们发现其他细胞类型也表现出许多相同的标记基因的零星表达，这表明存在一般的罕见细胞表达程序。
Therapies targeting signaling molecules mutated in cancers can often have striking short-term effects, but the emergence of resistant cancer cells is a major barrier to full cures. Resistance can result from a secondary mutations, but other times there is no clear genetic cause, raising the possibility of non-genetic rare cell variability. Here, we show that melanoma cells can display profound transcriptional variability at the single cell level that predicts which cells will ultimately resist drug treatment. This variability involves infrequent, semi-coordinated transcription of a number of resistance markers at high levels in a very small percentage of cells. The addition of drug then induces epigenetic reprogramming in these cells, converting the transient transcriptional state to a stably resistant state. This reprogramming begins with a loss of SOX10-mediated differentiation followed by activation of new signaling pathways, partially mediated by activity of Jun-AP-1 and TEAD. Our work reveals the multistage nature of the acquisition of drug resistance and provides a framework for understanding resistance dynamics in single cells. We find that other cell types also exhibit sporadic expression of many of these same marker genes, suggesting the existence of a general rare-cell expression program.
登录
查看更多内容
来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
48
作者：
Raj, Arjun;van den Bogaard, Patrick;Rifkin, Scott A.;van Oudenaarden, Alexander;Tyagi, Sanjay
通讯作者：
Tyagi, Sanjay
DOI：
10.1158/1078-0432.ccr-15-1762
发表时间：
2016-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Krepler C;Xiao M;Sproesser K;Brafford PA;Shannan B;Beqiri M;Liu Q;Xu W;Garman B;Nathanson KL;Xu X;Karakousis GC;Mills GB;Lu Y;Ahmed TA;Poulikakos PI;Caponigro G;Boehm M;Peters M;Schuchter LM;Weeraratna AT;Herlyn M
通讯作者：
Herlyn M
影响因子：
50.3
作者：
Roesch A;Vultur A;Bogeski I;Wang H;Zimmermann KM;Speicher D;Körbel C;Laschke MW;Gimotty PA;Philipp SE;Krause E;Pätzold S;Villanueva J;Krepler C;Fukunaga-Kalabis M;Hoth M;Bastian BC;Vogt T;Herlyn M
通讯作者：
Herlyn M
影响因子：
64.8
作者：
通讯作者：
--