Venteicher Andrew S, Tirosh Itay, Hebert Christine, Yizhak Keren, Neftel Cyril, Filbin Mariella G, Hovestadt Volker, Escalante Leah E, Shaw McKenzie L, Rodman Christopher, Gillespie Shawn M, Dionne Danielle, Luo Christina C, Ravichandran Hiranmayi, Mylvaganam Ravindra, Mount Christopher, Onozato Maristela L, Nahed Brian V, Wakimoto Hiroaki, Curry William T, Iafrate A John, Rivera Miguel N, Frosch Matthew P, Golub Todd R, Brastianos Priscilla K, Getz Gad, Patel Anoop P, Monje Michelle, Cahill Daniel P, Rozenblatt-Rosen Orit, Louis David N, Bernstein Bradley E, Regev Aviv, Suvà Mario L
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Science. 2017 Mar 31;355(6332). doi: 10.1126/science.aai8478.
Tumor subclasses differ according to the genotypes and phenotypes of malignant cells as well as the composition of the tumor microenvironment (TME). We dissected these influences in isocitrate dehydrogenase (IDH)-mutant gliomas by combining 14,226 single-cell RNA sequencing (RNA-seq) profiles from 16 patient samples with bulk RNA-seq profiles from 165 patient samples. Differences in bulk profiles between IDH-mutant astrocytoma and oligodendroglioma can be primarily explained by distinct TME and signature genetic events, whereas both tumor types share similar developmental hierarchies and lineages of glial differentiation. As tumor grade increases, we find enhanced proliferation of malignant cells, larger pools of undifferentiated glioma cells, and an increase in macrophage over microglia expression programs in TME. Our work provides a unifying model for IDH-mutant gliomas and a general framework for dissecting the differences among human tumor subclasses.
肿瘤亚类根据恶性细胞的基因型和表型以及肿瘤微环境（TME）的组成而有所不同。我们通过将来自16例患者样本的14226个单细胞RNA测序（RNA-seq）图谱与来自165例患者样本的批量RNA-seq图谱相结合，剖析了异柠檬酸脱氢酶（IDH）突变型胶质瘤中的这些影响因素。IDH突变型星形细胞瘤和少突胶质细胞瘤之间批量图谱的差异主要可由不同的TME和标志性遗传事件来解释，而这两种肿瘤类型具有相似的发育层次和神经胶质分化谱系。随着肿瘤分级增加，我们发现TME中恶性细胞增殖增强、未分化胶质瘤细胞池增大以及巨噬细胞相对于小胶质细胞表达程序增加。我们的工作为IDH突变型胶质瘤提供了一个统一模型，并为剖析人类肿瘤亚类之间的差异提供了一个通用框架。
