@article{f3c082a27418442da45425d3241cca00,
title = "Genetic screening for single-cell variability modulators driving therapy resistance",
abstract = "Cellular plasticity describes the ability of cells to transition from one set of phenotypes to another. In melanoma, transient fluctuations in the molecular state of tumor cells mark the formation of rare cells primed to survive BRAF inhibition and reprogram into a stably drug-resistant fate. However, the biological processes governing cellular priming remain unknown. We used CRISPR–Cas9 genetic screens to identify genes that affect cell fate decisions by altering cellular plasticity. We found that many factors can independently affect cellular priming and fate decisions. We discovered a new plasticity-based mode of increasing resistance to BRAF inhibition that pushes cells towards a more differentiated state. Manipulating cellular plasticity through inhibition of DOT1L before the addition of the BRAF inhibitor resulted in more therapy resistance than concurrent administration. Our results indicate that modulating cellular plasticity can alter cell fate decisions and may prove useful for treating drug resistance in other cancers.",
author = "Torre, {Eduardo A.} and Eri Arai and Sareh Bayatpour and Jiang, {Connie L.} and Beck, {Lauren E.} and Emert, {Benjamin L.} and Shaffer, {Sydney M.} and Mellis, {Ian A.} and Fane, {Mitchell E.} and Alicea, {Gretchen M.} and Budinich, {Krista A.} and Weeraratna, {Ashani T.} and Junwei Shi and Arjun Raj",
note = "Funding Information: We thank M. Herlyn for always providing excellent advice and guidance. We also thank the Flow Cytometry core team, especially F. Tuluc, at the Children{\textquoteright}s Hospital of Philadelphia for all their advice and help. We also thank all members of the Raj laboratory, as well as J. Murray, for their comments and suggestions. We thank C. Vakoc for providing the transcription factor, epigenetic regulator and kinase domain-focused sgRNA library. C.L.J. acknowledges the National Institutes of Health (NIH) awards T32 DK007780 and F30 HG010822. B.L.E. acknowledges support from NIH training grants F30 CA236129, T32 GM007170 and T32 HG000046. S.M.S. acknowledges support from DP5 OD028144. I.A.M. acknowledges funding from the NIH and the National Institute of Neurological Disorders (F30NS100595). A.T.W. and M.E.F. are supported by R01CA207935. A.T.W. and G.M.A. are supported by P01 CA114046, and A.T.W. is supported by CA227550, CA232256, the E.V. McCollum Chair and a Bloomberg Distinguished Professorship. Core facilities used in this grant are supported by P30CA010815 and P30CA006973. J.S. acknowledges support from the Linda Pechenik Montague Investigator Award and Cold Spring Harbor Laboratory sponsored research. A.R. acknowledges R01 CA238237, a NIH/National Cancer Institute Physical Science–Oncology Centers award (U54 CA193417), a National Science Foundation CAREER award (1350601), P30 CA016520, SPORE P50 CA174523, NIH U01 CA227550, NIH 4DN U01 HL129998, NIH Center for Photogenomics (RM1 HG007743) and the Tara Miller Foundation. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2021",
month = jan,
doi = "10.1038/s41588-020-00749-z",
language = "English (US)",
volume = "53",
pages = "76--85",
journal = "Nature genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "1",
}