Genetic screening for single-cell variability modulators driving therapy resistance.

Autor: Torre EA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Arai E; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Bayatpour S; Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA., Jiang CL; Genetics and Epigenetics, Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Beck LE; Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA., Emert BL; Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Shaffer SM; Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA.; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Mellis IA; Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Fane ME; Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, MD, USA., Alicea GM; Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, MD, USA., Budinich KA; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Weeraratna AT; Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, MD, USA.; Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA., Shi J; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. jushi@upenn.edu., Raj A; Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA. arjunraj@seas.upenn.edu.; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. arjunraj@seas.upenn.edu.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2021 Jan; Vol. 53 (1), pp. 76-85. Date of Electronic Publication: 2021 Jan 04.
DOI: 10.1038/s41588-020-00749-z
Abstrakt: 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.
Databáze: MEDLINE
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