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

Mei Chong Wendy Lee, Ferno J. Lopez-Diaz, Shahid Yar Khan, Muhammad Akram Tariq, Yelena Dayn, Charles Joseph Vaske, Amie J. Radenbaugh, Hyunsung John Kim, Beverly M. Emerson, Nader Pourm

Research output: Contribution to journalArticle

71 Scopus citations

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 drugtolerant 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.

Original languageEnglish (US)
Pages (from-to)E4726-E4735
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number44
DOIs
StatePublished - Nov 4 2014

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Keywords

  • Drug resistance |
  • Paclitaxel |
  • RNA-Seq
  • Single cell |
  • Tumor heterogeniety |

ASJC Scopus subject areas

  • General

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