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 () and Luca Magnani ()
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Sung Pil Hong: Imperial College London
Thalia E. Chan: Imperial College London
Ylenia Lombardo: Imperial College London
Giacomo Corleone: Imperial College London
Nicole Rotmensz: European Institute of Oncology and University of Milan, School of Medicine
Sara Bravaccini: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS
Andrea Rocca: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS
Giancarlo Pruneri: European Institute of Oncology and University of Milan, School of Medicine
Kirsten R. McEwen: Imperial College London
R. Charles Coombes: Imperial College London
Iros Barozzi: Imperial College London
Luca Magnani: Imperial College London

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11721-9

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