Description

Single Cell Analysis of Resistance to Cancer Drugs

Sydney Shaffer1 ,4 , Margaret Dunagin1 , Stefan Torborg1 ,2 , Eduardo A. Torre1 ,4 ,

Benjamin Emert4 ,8 , Clemens Krepler3 , Marilda Beqiri3 , Katrin Sproesser 3 ,

Patricia Brafford3 , Min Xiao3 , ElliottEggan4 , Ioannis N. Anastopoulos4 ,

Cesar A. Vargas-Garcia6 , Abhyudai Singh5 ,6 , Katherine Nathanson4 , Meenhard Herlyn3 , Arjun Raj1 ,7

1 Department of Bioengineering, University of Pennsylvania 2 Department of Biochemistry, University of Pennsylvania 3 The Wistar Institute, Molecular and Cellular Oncogenesis Program, Melanoma Research Center, Philadelphia, PA 4 Perelman School of Medicine, University of Pennsylvania 5 Biomedical Engineering, University of Delaware, Newark, DE, USA 6 Electrical and Computer Engineering, University of Delaware, Newark, DE, USA 7 Department of Genetics, University of Pennsylvania 8 Genomics and Computational Biology Group, University of Pennsylvania

Cancer is a disease of single cells behaving badly, with mutations to certain proteins causing uncontrolled cellular proliferation. This has led to the development of therapies targeting those proteins, such as vemurafenib for melanoma. Yet while most cells will respond to drug, some do not, ultimately repopulating the tumors and causing relapse. This process is often thought to be Darwinian with genetic origins as well. Here, we show that the acquisition of resistance may have in fact have non-genetic origins, and we decompose the resistance process into an early, transient priming phase before the addition of drug, following by a later reprogramming phase consisting of a stepwise epigenetic progression. We discuss some implications for cancer treatment as well as cell fate plasticity.