Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma.
Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma.
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DOI：
10.1038/nature20123
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发表时间：
2016-11-10
期刊：
影响因子：
64.8
通讯作者：
Suvà ML
中科院分区：
文献类型：
--
作者：
Tirosh I;Venteicher AS;Hebert C;Escalante LE;Patel AP;Yizhak K;Fisher JM;Rodman C;Mount C;Filbin MG;Neftel C;Desai N;Nyman J;Izar B;Luo CC;Francis JM;Patel AA;Onozato ML;Riggi N;Livak KJ;Gennert D;Satija R;Nahed BV;Curry WT;Martuza RL;Mylvaganam R;Iafrate AJ;Frosch MP;Golub TR;Rivera MN;Getz G;Rozenblatt-Rosen O;Cahill DP;Monje M;Bernstein BE;Louis DN;Regev A;Suvà ML
虽然人类肿瘤是由癌细胞的遗传进化形成的，但有证据表明，它们显示出与发育途径和表观遗传程序相关的层次结构，其中癌症干细胞（CSC）可以驱动肿瘤生长并产生分化的后代。然而，CSC在实体人类恶性肿瘤中的无偏见证据仍然难以捉摸。在这里，我们通过RNA测序（RNA-seq）分析了来自6个IDH 1或IDH 2突变型人类少突胶质细胞瘤的4，347个单细胞，并从全基因组表达特征中重建了它们的发育程序。我们推断，大多数癌细胞分化沿着两个专门的胶质细胞程序，而一个罕见的细胞亚群是未分化的，并与神经干细胞表达程序。具有增殖表达特征的细胞在这种罕见的亚群中高度富集，这与CSC主要负责促进人类少突胶质细胞瘤生长的模型一致。拷贝数变异（CNV）的分析表明，不同的CNV亚克隆肿瘤内显示类似的细胞层次结构，这表明少突胶质细胞瘤的架构主要是由发展计划。亚克隆点突变分析支持一个类似的模型，虽然一个完整的系统发育树将需要明确地确定推断层次的遗传进化的影响。我们的单细胞分析提供了对少突胶质细胞瘤单细胞分辨率的细胞结构的深入了解，并支持癌症干细胞模型，对疾病管理具有重大意义。
Although human tumours are shaped by the genetic evolution of cancer cells, evidence also suggests that they display hierarchies related to developmental pathways and epigenetic programs in which cancer stem cells (CSCs) can drive tumour growth and give rise to differentiated progeny. Yet, unbiased evidence for CSCs in solid human malignancies remains elusive. Here we profile 4,347 single cells from six IDH1 or IDH2 mutant human oligodendrogliomas by RNA sequencing (RNA-seq) and reconstruct their developmental programs from genome-wide expression signatures. We infer that most cancer cells are differentiated along two specialized glial programs, whereas a rare subpopulation of cells is undifferentiated and associated with a neural stem cell expression program. Cells with expression signatures for proliferation are highly enriched in this rare subpopulation, consistent with a model in which CSCs are primarily responsible for fuelling the growth of oligodendroglioma in humans. Analysis of copy number variation (CNV) shows that distinct CNV sub-clones within tumours display similar cellular hierarchies, suggesting that the architecture of oligodendroglioma is primarily dictated by developmental programs. Subclonal point mutation analysis supports a similar model, although a full phylogenetic tree would be required to definitively determine the effect of genetic evolution on the inferred hierarchies. Our single-cell analyses provide insight into the cellular architecture of oligodendrogliomas at single-cell resolution and support the cancer stem cell model, with substantial implications for disease management.