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

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.

• Authors: Sydney M Shaffer, Margaret C Dunagin, Stefan R Torborg, Eduardo A Torre, Benjamin Emert, Clemens Krepler, Marilda Beqiri, Katrin Sproesser, Patricia A Brafford, Min Xiao, Elliott Eggan, Ioannis N Anastopoulos, Cesar A Vargas-Garcia, Abhyudai Singh, Katherine L Nathanson, Meenhard Herlyn, Arjun Raj
• Journal: Nature (Nature) Vol. 546 Issue 7658 Pg. 431-435 (06 15 2017) ISSN: 1476-4687 [Electronic] England
• PMID: 28607484 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

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

Topics

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