Unravelling subclonal heterogeneity and aggressive disease states in TNBC through single-cell RNA-seq.
Unravelling subclonal heterogeneity and aggressive disease states in TNBC through single-cell RNA-seq.
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DOI：
10.1038/s41467-018-06052-0
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发表时间：
2018-09-04
影响因子：
16.6
通讯作者：
Ellisen LW
中科院分区：
文献类型：
--
作者：
Karaayvaz M;Cristea S;Gillespie SM;Patel AP;Mylvaganam R;Luo CC;Specht MC;Bernstein BE;Michor F;Ellisen LW
三阴性乳腺癌（TNBC）是一种以广泛的肿瘤内异质性为特征的侵袭性亚型。为了研究潜在的生物学，我们对来自六个原代TNBC的>1500个细胞进行单细胞RNA测序（scRNA-seq）。在这里，我们表明，每个肿瘤内的基因表达程序的细胞间异质性是可变的，并在很大程度上与推断的基因组拷贝数变化的克隆性相关，这表明基因型驱动的基因表达表型的个别亚群。基因表达谱的聚类鉴定了多种肿瘤共有的恶性细胞的不同亚群，包括与治疗抗性和转移的多个特征相关的单个亚群，并且功能上以鞘糖脂代谢和相关先天免疫途径的激活为特征。定义该亚群的新特征预测了大型队列中TNBC患者的长期结局。总的来说，该分析揭示了TNBC中的功能异质性及其与基因组进化的关联，并揭示了决定这种疾病不良结局的意外生物学原理。三阴性乳腺癌具有高度异质性和侵袭性。在这里，作者利用单细胞RNA测序来研究这种异质性，并发现了与转移和治疗抗性特征相关的细胞亚群，并与长期生存结果相关。
Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by extensive intratumoral heterogeneity. To investigate the underlying biology, we conducted single-cell RNA-sequencing (scRNA-seq) of >1500 cells from six primary TNBC. Here, we show that intercellular heterogeneity of gene expression programs within each tumor is variable and largely correlates with clonality of inferred genomic copy number changes, suggesting that genotype drives the gene expression phenotype of individual subpopulations. Clustering of gene expression profiles identified distinct subgroups of malignant cells shared by multiple tumors, including a single subpopulation associated with multiple signatures of treatment resistance and metastasis, and characterized functionally by activation of glycosphingolipid metabolism and associated innate immunity pathways. A novel signature defining this subpopulation predicts long-term outcomes for TNBC patients in a large cohort. Collectively, this analysis reveals the functional heterogeneity and its association with genomic evolution in TNBC, and uncovers unanticipated biological principles dictating poor outcomes in this disease. Triple-negative breast cancer is highly heterogeneous and aggressive. Here, the authors utilise single-cell RNA sequencing to investigate this heterogeneity, and discover a subpopulation of cells associated with metastasis and treatment resistance signatures, and linked to long term survival outcomes.
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影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
16.6
作者：
Gao R;Kim C;Sei E;Foukakis T;Crosetto N;Chan LK;Srinivasan M;Zhang H;Meric-Bernstam F;Navin N
通讯作者：
Navin N
DOI：
10.1158/1078-0432.ccr-16-2363
发表时间：
2017-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Britten CD;Garrett-Mayer E;Chin SH;Shirai K;Ogretmen B;Bentz TA;Brisendine A;Anderton K;Cusack SL;Maines LW;Zhuang Y;Smith CD;Thomas MB
通讯作者：
Thomas MB
影响因子：
45.3
作者：
Adams, Sylvia;Gray, Robert J.;Badve, Sunil S.
通讯作者：
Badve, Sunil S.