Single-cell transcriptomics reveals multi-step adaptations to endocrine therapy: Nature Communications

S.P. Hong, T.E. Chan, Y. Lombardo, G. Corleone, N. Rotmensz, S. Bravaccini, A. Rocca, G. Pruneri, K.R. McEwen, R.C. Coombes, I. Barozzi, L. Magnani

Research output: Contribution to journalArticle

Abstract

Resistant tumours are thought to arise from the action of Darwinian selection on genetically heterogenous cancer cell populations. However, simple clonal selection is inadequate to describe the late relapses often characterising luminal breast cancers treated with endocrine therapy (ET), suggesting a more complex interplay between genetic and non-genetic factors. Here, we dissect the contributions of clonal genetic diversity and transcriptional plasticity during the early and late phases of ET at single-cell resolution. Using single-cell RNA-sequencing and imaging we disentangle the transcriptional variability of plastic cells and define a rare subpopulation of pre-adapted (PA) cells which undergoes further transcriptomic reprogramming and copy number changes to acquire full resistance. We find evidence for sub-clonal expression of a PA signature in primary tumours and for dominant expression in clustered circulating tumour cells. We propose a multi-step model for ET resistance development and advocate the use of stage-specific biomarkers. © 2019, The Author(s).
Original languageEnglish
JournalNat. Commun.
Volume10
Issue number1
DOIs
Publication statusPublished - 2019

Keywords

  • biological marker
  • cell surface protein
  • antineoplastic hormone agonists and antagonists
  • estrogen receptor alpha
  • estrogen receptor alpha, human
  • transcriptome
  • biomarker
  • cancer
  • cell
  • disease treatment
  • endocrine system
  • genetic analysis
  • RNA
  • area under the curve
  • Article
  • breast cancer
  • cell subpopulation
  • circulating tumor cell
  • controlled study
  • copy number variation
  • CYP19A1 gene
  • fluorescence activated cell sorting
  • gene
  • gene amplification
  • gene expression
  • gene regulatory network
  • genetic variability
  • hormonal therapy
  • human
  • human cell
  • immunofluorescence
  • live cell imaging
  • primary tumor
  • RNA sequence
  • single cell analysis
  • solid malignant neoplasm
  • tissue microarray
  • transcriptomics
  • blood
  • breast
  • breast tumor
  • cell plasticity
  • cytology
  • drug effect
  • drug resistance
  • female
  • gene expression regulation
  • genetics
  • intravital microscopy
  • machine learning
  • MCF-7 cell line
  • metabolism
  • multicellular spheroid
  • mutation
  • pathology
  • tumor embolism
  • Antineoplastic Agents, Hormonal
  • Breast
  • Breast Neoplasms
  • Cell Plasticity
  • Drug Resistance, Neoplasm
  • Estrogen Receptor alpha
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intravital Microscopy
  • Machine Learning
  • MCF-7 Cells
  • Mutation
  • Neoplastic Cells, Circulating
  • RNA-Seq
  • Single-Cell Analysis
  • Spheroids, Cellular
  • Transcriptome

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