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

• Published in: Nature communications Vol. 10; no. 1; pp. 3840 - 14
• Main Authors: Hong, Sung Pil, Chan, Thalia E., Lombardo, Ylenia, Corleone, Giacomo, Rotmensz, Nicole, Bravaccini, Sara, Rocca, Andrea, Pruneri, Giancarlo, McEwen, Kirsten R., Coombes, R. Charles, Barozzi, Iros, Magnani, Luca
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02-09-2019; Nature Publishing Group; Nature Portfolio
• Subjects: 45; 45/91; 631/114/2397; 631/67/1059/2326; 631/67/1347; 631/80/304; Adaptation; Antineoplastic Agents, Hormonal - pharmacology; Antineoplastic Agents, Hormonal - therapeutic use; Biomarkers; Breast; Breast - cytology; Breast - pathology; Breast cancer; Breast Neoplasms - blood; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Cell Plasticity - drug effects; Cell Plasticity - genetics; Clonal selection; Copy number; Drug Resistance, Neoplasm - genetics; Endocrine therapy; Estrogen Receptor alpha - metabolism; Female; Gene Expression Regulation, Neoplastic - drug effects; Gene sequencing; Genetic diversity; Genetic factors; Humanities and Social Sciences; Humans; Intravital Microscopy; Machine Learning; MCF-7 Cells; multidisciplinary; Mutation; Neoplastic Cells, Circulating - drug effects; Plasticity; Ribonucleic acid; RNA; RNA-Seq; Science; Science (multidisciplinary); Single-Cell Analysis; Spheroids, Cellular; Therapy; Transcription; Transcriptome - drug effects; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11721-9

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.
The development of resistance to endocrine therapy is a significant, clinical problem in breast cancer. Here, the authors identify a rare subpopulation of cells that drive resistance following transcriptional reprogramming.