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Single-cell analyses of transcriptional heterogeneity during drug tolerance transition in cancer cells by RNA sequencing.

Authors
  • Lee, Mei-Chong Wendy1
  • Lopez-Diaz, Fernando J2
  • Khan, Shahid Yar1
  • Tariq, Muhammad Akram1
  • Dayn, Yelena3
  • Vaske, Charles Joseph4
  • Radenbaugh, Amie J1
  • Kim, Hyunsung John1
  • Emerson, Beverly M5
  • Pourmand, Nader6
  • 1 Biomolecular Engineering Department, University of California, Santa Cruz, CA 95064;
  • 2 Laboratory of Regulatory Biology, The Salk Institute for Biological Studies, La Jolla, CA 92037;
  • 3 Transgenic Core Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037; and.
  • 4 Five3 Genomics, LLC, Santa Cruz, CA 95060.
  • 5 Laboratory of Regulatory Biology, The Salk Institute for Biological Studies, La Jolla, CA 92037; [email protected] [email protected]
  • 6 Biomolecular Engineering Department, University of California, Santa Cruz, CA 95064; [email protected] [email protected]
Type
Published Article
Journal
Proceedings of the National Academy of Sciences
Publisher
Proceedings of the National Academy of Sciences
Publication Date
Nov 04, 2014
Volume
111
Issue
44
Identifiers
DOI: 10.1073/pnas.1404656111
PMID: 25339441
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The acute cellular response to stress generates a subpopulation of reversibly stress-tolerant cells under conditions that are lethal to the majority of the population. Stress tolerance is attributed to heterogeneity of gene expression within the population to ensure survival of a minority. We performed whole transcriptome sequencing analyses of metastatic human breast cancer cells subjected to the chemotherapeutic agent paclitaxel at the single-cell and population levels. Here we show that specific transcriptional programs are enacted within untreated, stressed, and drug-tolerant cell groups while generating high heterogeneity between single cells within and between groups. We further demonstrate that drug-tolerant cells contain specific RNA variants residing in genes involved in microtubule organization and stabilization, as well as cell adhesion and cell surface signaling. In addition, the gene expression profile of drug-tolerant cells is similar to that of untreated cells within a few doublings. Thus, single-cell analyses reveal the dynamics of the stress response in terms of cell-specific RNA variants driving heterogeneity, the survival of a minority population through generation of specific RNA variants, and the efficient reconversion of stress-tolerant cells back to normalcy.

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