Sydney M. Shaffer 1 , 4 , Margaret C. Dunagin 1 , Stefan R. Torborg 1 , 2 , Eduardo A. Torre 1 , 4 , Benjamin Emert 4 , 8 , Clemens Krepler 3 , Marilda Beqiri 3 , Katrin Sproesser 3 , Patricia A. Brafford 3 , Min Xiao 3 , Elliott Eggan 4 , Ioannis N. Anastopoulos 4 , Cesar A. Vargas-Garcia 6 , Abhyudai Singh 5 , 6 , Katherine L. Nathanson 4 , Meenhard Herlyn 3 , Arjun Raj 1 , 7
07 June 2017
Therapies targeting signaling molecules mutated in cancers can often have striking short-term effects, but the emergence of resistant cancer cells is a major barrier to full cures 1, 2 . Resistance can result from a secondary mutations 3, 4 , but other times there is no clear genetic cause, raising the possibility of non-genetic rare cell variability 5– 11 . Here, we show that 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 signaling pathways, partially mediated by activity of Jun-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 rare-cell expression program.