Department of Surgery and Cancer, Imperial College London, London, UK.
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
Nat Commun. 2019 Sep 2;10(1):3840. 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.
耐药肿瘤被认为是达尔文选择作用于遗传异质性癌细胞群体的结果。然而，简单的克隆选择不足以描述接受内分泌治疗（ET）的腔型乳腺癌经常出现的晚期复发，这表明遗传和非遗传因素之间存在更复杂的相互作用。在这里，我们在单细胞分辨率下解析了克隆遗传多样性和转录可塑性在 ET 的早期和晚期阶段的贡献。我们使用单细胞 RNA 测序和成像技术，分离出可塑性细胞的转录可变性，并定义了一个罕见的预先适应（PA）细胞亚群，这些细胞经历进一步的转录组重编程和拷贝数变化以获得完全耐药性。我们在原发肿瘤中发现了 PA 特征的亚克隆表达的证据，并在聚集的循环肿瘤细胞中发现了优势表达。我们提出了一个用于 ET 耐药发展的多步骤模型，并提倡使用阶段特异性生物标志物。
