期刊
NATURE
卷 546, 期 7658, 页码 431-+出版社
NATURE PORTFOLIO
DOI: 10.1038/nature22794
关键词
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资金
- NIH [DP2 OD008514, R33 EB019767, P30 CA016520, F30 AI114475]
- NIH/NCI PSOC [U54 CA193417]
- NSF CAREER [1350601]
- National Science Foundation [DMS-1312926]
- SPORE [P50 CA174523]
- Melanoma Research Foundation
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- [P01 CA114046]
- [R01 CA047159]
- Division Of Mathematical Sciences
- Direct For Mathematical & Physical Scien [1312926] Funding Source: National Science Foundation
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1350601] Funding Source: National Science Foundation
Therapies that target signalling molecules that are mutated in cancers can often have substantial short-term effects, but the emergence of resistant cancer cells is a major barrier to full cures(1,2). Resistance can result from secondary mutations(3,4), but in other cases there is no clear genetic cause, raising the possibility of non-genetic rare cell variability(5-11). Here we show that human 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 signalling pathways, partially mediated by the activity of the transcription factors JUN and/ or 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 program in which expression is displayed in rare subpopulations of cells.
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