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Genetic screening for single-cell variability modulators driving therapy resistance

View ORCID ProfileEduardo A. Torre, Eri Arai, Sareh Bayatpour, Lauren E. Beck, View ORCID ProfileBenjamin L. Emert, View ORCID ProfileSydney M. Shaffer, View ORCID ProfileIan A. Mellis, Mitchell Fane, Gretchen Alicea, Krista A. Budinich, View ORCID ProfileAshani Weeraratna, View ORCID ProfileJunwei Shi, View ORCID ProfileArjun Raj
doi: https://doi.org/10.1101/638809
Eduardo A. Torre
1Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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Eri Arai
3Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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Sareh Bayatpour
2Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA
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Lauren E. Beck
2Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA
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Benjamin L. Emert
6Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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Sydney M. Shaffer
2Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA
5Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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Ian A. Mellis
6Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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Mitchell Fane
4The Wistar Institute, Philadelphia, PA
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Gretchen Alicea
4The Wistar Institute, Philadelphia, PA
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Krista A. Budinich
3Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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Ashani Weeraratna
8Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD
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Junwei Shi
3Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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  • For correspondence: arjunraj@seas.upenn.edu
Arjun Raj
2Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA
3Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
7Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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  • For correspondence: arjunraj@seas.upenn.edu
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Abstract

Cellular plasticity describes the ability of cells to transition from one set of phenotypes to another. In the context of cancer therapeutics, plasticity refers to transient fluctuations in the molecular state of tumor cells, driving the formation of rare cells primed to survive drug treatment and ultimately reprogram into a stably resistant fate. However, the biological processes governing this cellular plasticity remain unknown. We used CRISPR/Cas9 genetic screens to reveal genes that affect cell fate decisions by altering cellular plasticity across a range of functional categories. We found that cellular plasticity and cell fate decision making can be decoupled in that factors can affect cell fate decisions in both plasticity-dependent and independent manners. We discovered a novel mode of altering resistance based on cellular plasticity that, contrary to known mechanisms, pushes cells towards a more differentiated state. We further confirmed our prediction that manipulating cellular plasticity before the addition of the main therapy would result in changes in therapy resistance more than concurrent administration. Together, our results indicate that identifying pathways modulating cellular plasticity has the potential to alter cell fate decisions and may provide a new avenue for treating drug resistance.

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Posted November 10, 2019.
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Genetic screening for single-cell variability modulators driving therapy resistance
Eduardo A. Torre, Eri Arai, Sareh Bayatpour, Lauren E. Beck, Benjamin L. Emert, Sydney M. Shaffer, Ian A. Mellis, Mitchell Fane, Gretchen Alicea, Krista A. Budinich, Ashani Weeraratna, Junwei Shi, Arjun Raj
bioRxiv 638809; doi: https://doi.org/10.1101/638809
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Genetic screening for single-cell variability modulators driving therapy resistance
Eduardo A. Torre, Eri Arai, Sareh Bayatpour, Lauren E. Beck, Benjamin L. Emert, Sydney M. Shaffer, Ian A. Mellis, Mitchell Fane, Gretchen Alicea, Krista A. Budinich, Ashani Weeraratna, Junwei Shi, Arjun Raj
bioRxiv 638809; doi: https://doi.org/10.1101/638809

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