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Nature. 2017 Jun 15;546(7658):431-435. doi: 10.1038/nature22794. Epub 2017 Jun 7.

Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance.

Author information

1
Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
2
Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
3
Department of Biochemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
4
Genomics and Computational Biology Group, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
5
The Wistar Institute, Molecular and Cellular Oncogenesis Program, Melanoma Research Center, Philadelphia, Pennsylvania 19104, USA.
6
Electrical and Computer Engineering, University of Delaware, Newark, Delaware 19716, USA.
7
Biomedical Engineering, University of Delaware, Newark, Delaware 19716, USA.
8
Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Abstract

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. Resistance can result from secondary mutations, but in other cases there is no clear genetic cause, raising the possibility of non-genetic rare cell variability. 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.

PMID:
28607484
PMCID:
PMC5542814
DOI:
10.1038/nature22794
[Indexed for MEDLINE]
Free PMC Article

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