Chemoresistance Evolution in Triple-Negative Breast Cancer Delineated by Single-Cell Sequencing

Charissa Kim, Ruli Gao, Emi Sei, Rachel Brandt, Johan Hartman, Thomas Hatschek, Nicola Crosetto, Theodoros Foukakis, Nicholas E. Navin

Research output: Contribution to journalArticle

213 Scopus citations

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype that frequently develops resistance to chemotherapy. An unresolved question is whether resistance is caused by the selection of rare pre-existing clones or alternatively through the acquisition of new genomic aberrations. To investigate this question, we applied single-cell DNA and RNA sequencing in addition to bulk exome sequencing to profile longitudinal samples from 20 TNBC patients during neoadjuvant chemotherapy (NAC). Deep-exome sequencing identified 10 patients in which NAC led to clonal extinction and 10 patients in which clones persisted after treatment. In 8 patients, we performed a more detailed study using single-cell DNA sequencing to analyze 900 cells and single-cell RNA sequencing to analyze 6,862 cells. Our data showed that resistant genotypes were pre-existing and adaptively selected by NAC, while transcriptional profiles were acquired by reprogramming in response to chemotherapy in TNBC patients. Combination of single-cell DNA and RNA sequencing depicts the evolutionary trajectories of chemoresistance in human triple-negative breast cancer at the genomic and transcriptomic level, highlighting the presence of pre-existing genomic alterations and transcriptional reprogramming of resistant signatures.

Original languageEnglish (US)
Pages (from-to)879-893.e13
JournalCell
Volume173
Issue number4
DOIs
StatePublished - May 3 2018

Keywords

  • breast cancer genomics
  • cancer aneuploidy
  • chemotherapy
  • copy-number evolution
  • intratumor heterogeneity
  • single-cell sequencing
  • therapy resistance
  • triple-negative breast cancer
  • tumor evolution

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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