Transcriptome analysis reveals tumor microenvironment changes in glioblastoma
Transcriptome analysis reveals tumor microenvironment changes in glioblastoma
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DOI：
10.1016/j.ccell.2023.02.019
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发表时间：
2023-04-10
期刊：
影响因子：
50.3
通讯作者：
French, Pim J.
中科院分区：
文献类型：
--
作者：
Hoogstrate, Youri;Draaisma, Kaspar;French, Pim J.
更好地理解异柠檬酸脱氢酶（IDH）野生型胶质母细胞瘤的转录演变对于优化治疗可能至关重要。在此，我们对接受当前标准治疗的患者的配对原发性 - 复发性胶质母细胞瘤切除样本进行RNA测序（RNA - seq）（测试组n = 322，验证组n = 245）。转录亚型在二维空间中形成一个相互关联的连续体。复发性肿瘤显示出优先的间充质进展。随着时间推移，标志性的胶质母细胞瘤基因没有显著改变。相反，肿瘤纯度随着时间降低，并且伴随着神经元和少突胶质细胞标记基因的共同增加，以及肿瘤相关巨噬细胞的独立增加。内皮标记基因出现降低。这些组成变化通过单细胞RNA - seq和免疫组织化学得到证实。一个细胞外基质相关基因集在复发时增加，大量样本、单细胞RNA以及免疫组织化学表明它主要由周细胞表达。这一特征与复发时显著更差的生存率相关。我们的数据表明，胶质母细胞瘤主要通过微环境（重新）组织而非肿瘤细胞的分子演变而进展。
A better understanding of transcriptional evolution of IDH-wild-type glioblastoma may be crucial for treatment optimization. Here, we perform RNA sequencing (RNA-seq) (n = 322 test, n = 245 validation) on paired primary-recurrent glioblastoma resections of patients treated with the current standard of care. Transcriptional subtypes form an interconnected continuum in a two-dimensional space. Recur-rent tumors show preferential mesenchymal progression. Over time, hallmark glioblastoma genes are not significantly altered. Instead, tumor purity decreases over time and is accompanied by co -in-creases in neuron and oligodendrocyte marker genes and, independently, tumor-associated macro-phages. A decrease is observed in endothelial marker genes. These composition changes are confirmed by single-cell RNA-seq and immunohistochemistry. An extracellular matrix-associated gene set increases at recurrence and bulk, single-cell RNA, and immunohistochemistry indicate it is expressed mainly by pericytes. This signature is associated with significantly worse survival at recur-rence. Our data demonstrate that glioblastomas evolve mainly by microenvironment (re-)organization rather than molecular evolution of tumor cells.