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

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

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cellular Reprogramming / drug effects*
  • Cellular Reprogramming / genetics*
  • DNA-Binding Proteins / metabolism
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics*
  • Epigenesis, Genetic / drug effects
  • ErbB Receptors / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Genetic Markers / drug effects
  • Genetic Markers / genetics
  • Humans
  • In Situ Hybridization, Fluorescence
  • Indoles / pharmacology
  • Male
  • Melanoma / genetics*
  • Melanoma / pathology*
  • Nuclear Proteins / metabolism
  • Oncogene Protein p65(gag-jun) / metabolism
  • SOXE Transcription Factors / deficiency
  • SOXE Transcription Factors / genetics
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Single-Cell Analysis
  • Sulfonamides / pharmacology
  • Transcription Factor AP-1 / metabolism
  • Transcription Factors / metabolism
  • Transcription, Genetic / drug effects
  • Vemurafenib
  • Xenograft Model Antitumor Assays

Substances

  • DNA-Binding Proteins
  • Genetic Markers
  • Indoles
  • Nuclear Proteins
  • Oncogene Protein p65(gag-jun)
  • SOX10 protein, human
  • SOXE Transcription Factors
  • Sulfonamides
  • TEAD1 protein, human
  • Transcription Factor AP-1
  • Transcription Factors
  • Vemurafenib
  • EGFR protein, human
  • ErbB Receptors