Title | Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | 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 |
Journal | Nature |
Volume | 546 |
Issue | 7658 |
Pagination | 431-435 |
Date Published | 2017 06 15 |
ISSN | 1476-4687 |
Keywords | Animals, Cell Line, Tumor, Cellular Reprogramming, DNA-Binding Proteins, Drug Resistance, Neoplasm, Epigenesis, Genetic, ErbB Receptors, Female, Gene Expression Regulation, Neoplastic, Genetic Markers, Humans, In Situ Hybridization, Fluorescence, Indoles, Male, Melanoma, Nuclear Proteins, Oncogene Protein p65(gag-jun), Signal Transduction, Single-Cell Analysis, SOXE Transcription Factors, Sulfonamides, Transcription Factor AP-1, Transcription Factors, Transcription, Genetic, Vemurafenib, Xenograft Model Antitumor Assays |
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. |
DOI | 10.1038/nature22794 |
Alternate Journal | Nature |
PubMed ID | 28607484 |
PubMed Central ID | PMC5542814 |
Grant List | P30 CA016672 / CA / NCI NIH HHS / United States P30 CA010815 / CA / NCI NIH HHS / United States P01 CA114046 / CA / NCI NIH HHS / United States F30 AI114475 / AI / NIAID NIH HHS / United States U54 CA193417 / CA / NCI NIH HHS / United States P50 CA174523 / CA / NCI NIH HHS / United States P30 CA016520 / CA / NCI NIH HHS / United States DP2 OD008514 / OD / NIH HHS / United States T32 HG000046 / HG / NHGRI NIH HHS / United States R01 CA047159 / CA / NCI NIH HHS / United States R33 EB019767 / EB / NIBIB NIH HHS / United States |
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