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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Cell Line, Tumor
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Cellular Reprogramming / drug effects*
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Cellular Reprogramming / genetics*
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DNA-Binding Proteins / metabolism
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Drug Resistance, Neoplasm / drug effects*
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Drug Resistance, Neoplasm / genetics*
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Epigenesis, Genetic / drug effects
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ErbB Receptors / metabolism
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Female
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Gene Expression Regulation, Neoplastic / drug effects*
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Genetic Markers / drug effects
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Genetic Markers / genetics
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Humans
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In Situ Hybridization, Fluorescence
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Indoles / pharmacology
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Male
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Melanoma / genetics*
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Melanoma / pathology*
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Nuclear Proteins / metabolism
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Oncogene Protein p65(gag-jun) / metabolism
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SOXE Transcription Factors / deficiency
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SOXE Transcription Factors / genetics
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Single-Cell Analysis
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Sulfonamides / pharmacology
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TEA Domain Transcription Factors
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Transcription Factor AP-1 / metabolism
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Transcription Factors / metabolism
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Transcription, Genetic / drug effects
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Vemurafenib
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Xenograft Model Antitumor Assays
Substances
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DNA-Binding Proteins
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Genetic Markers
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Indoles
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Nuclear Proteins
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Oncogene Protein p65(gag-jun)
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SOX10 protein, human
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SOXE Transcription Factors
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Sulfonamides
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TEA Domain Transcription Factors
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TEAD1 protein, human
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Transcription Factor AP-1
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Transcription Factors
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Vemurafenib
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EGFR protein, human
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ErbB Receptors