Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Variability within rare cell states enables multiple paths towards drug resistance

View ORCID ProfileBenjamin L. Emert, Christopher Cote, View ORCID ProfileEduardo A. Torre, Ian P. Dardani, View ORCID ProfileConnie L. Jiang, Naveen Jain, View ORCID ProfileSydney M. Shaffer, View ORCID ProfileArjun Raj
doi: https://doi.org/10.1101/2020.03.18.996660
Benjamin L. Emert
1Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Benjamin L. Emert
Christopher Cote
2Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
3Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eduardo A. Torre
4Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Eduardo A. Torre
Ian P. Dardani
3Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Connie L. Jiang
5Genetics and Epigenetics, Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Connie L. Jiang
Naveen Jain
5Genetics and Epigenetics, Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sydney M. Shaffer
3Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA
6Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
7Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Sydney M. Shaffer
Arjun Raj
2Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
3Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Arjun Raj
  • For correspondence: arjunrajlab@gmail.com
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Data/Code
  • Preview PDF
Loading

Abstract

Molecular differences between individual cells can lead to dramatic differences in cell fate, such as death versus survival of cancer cells upon drug treatment. These originating differences remain largely hidden due to difficulties in determining precisely what variable molecular features lead to which cellular fates. Thus, we developed Rewind, a methodology that combines genetic barcoding with RNA FISH to directly capture rare cells that give rise to cellular behaviors of interest. Applied to BRAFV600E melanoma, we trace drug-resistant cell fates back to single-cell gene expression differences in their drug-naive precursors (initial frequency of ∼1:1000-1:10,000 cells) and relative persistence of MAP-kinase signaling soon after drug treatment. Within this rare subpopulation, we uncover a rich substructure in which molecular differences between several distinct subpopulations predict future differences in phenotypic behavior, such as proliferative capacity of distinct resistant clones following drug treatment. Similarly, we show that treatments that modify the frequency of resistance can allow otherwise non-resistant cells in the drug-naive population to become resistant, and that these new populations are marked by the variable expression of distinct genes. Together, our results reveal the presence of hidden, rare-cell variability that can underlie a range of latent phenotypic outcomes upon drug exposure.

Competing Interest Statement

AR receives consulting income and AR and SMS receive royalties related to Stellaris RNA FISH probes.

Footnotes

  • https://www.dropbox.com/sh/mmeg3mckrpridu3/AAALBaMLoJsJiQC2-lrVY0Cva?dl=0

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
Back to top
PreviousNext
Posted December 23, 2020.
Download PDF

Supplementary Material

Data/Code
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Variability within rare cell states enables multiple paths towards drug resistance
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Variability within rare cell states enables multiple paths towards drug resistance
Benjamin L. Emert, Christopher Cote, Eduardo A. Torre, Ian P. Dardani, Connie L. Jiang, Naveen Jain, Sydney M. Shaffer, Arjun Raj
bioRxiv 2020.03.18.996660; doi: https://doi.org/10.1101/2020.03.18.996660
Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
Citation Tools
Variability within rare cell states enables multiple paths towards drug resistance
Benjamin L. Emert, Christopher Cote, Eduardo A. Torre, Ian P. Dardani, Connie L. Jiang, Naveen Jain, Sydney M. Shaffer, Arjun Raj
bioRxiv 2020.03.18.996660; doi: https://doi.org/10.1101/2020.03.18.996660

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Systems Biology
Subject Areas
All Articles
  • Animal Behavior and Cognition (2635)
  • Biochemistry (5224)
  • Bioengineering (3650)
  • Bioinformatics (15730)
  • Biophysics (7218)
  • Cancer Biology (5597)
  • Cell Biology (8051)
  • Clinical Trials (138)
  • Developmental Biology (4739)
  • Ecology (7472)
  • Epidemiology (2059)
  • Evolutionary Biology (10531)
  • Genetics (7704)
  • Genomics (10090)
  • Immunology (5157)
  • Microbiology (13829)
  • Molecular Biology (5354)
  • Neuroscience (30605)
  • Paleontology (212)
  • Pathology (872)
  • Pharmacology and Toxicology (1520)
  • Physiology (2235)
  • Plant Biology (4987)
  • Scientific Communication and Education (1037)
  • Synthetic Biology (1380)
  • Systems Biology (4131)
  • Zoology (804)