Single-cell transcriptomics reveals multi-step adaptations to endocrine therapy

Sung Pil Hong, Thalia E. Chan, Ylenia Lombardo, Giacomo Corleone, Nicole Rotmensz, Sara Bravaccini, Andrea Rocca, Giancarlo Pruneri, Kirsten R. McEwen, R. Charles Coombes, Iros Barozzi, Luca 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.

Original languageEnglish
Article number3840
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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  • Cite this

    Hong, S. P., Chan, T. E., Lombardo, Y., Corleone, G., Rotmensz, N., Bravaccini, S., Rocca, A., Pruneri, G., McEwen, K. R., Coombes, R. C., Barozzi, I., & Magnani, L. (2019). Single-cell transcriptomics reveals multi-step adaptations to endocrine therapy. Nature Communications, 10(1), [3840]. https://doi.org/10.1038/s41467-019-11721-9