CD90 Expression Controls Migration and Predicts Dasatinib Response in Glioblastoma
CD90 Expression Controls Migration and Predicts Dasatinib Response in Glioblastoma
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DOI：
10.1158/1078-0432.ccr-17-1549
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发表时间：
2017-12-01
影响因子：
11.5
通讯作者：
Quillien, Veronique
中科院分区：
文献类型：
--
作者：
Avril, Tony;Etcheverry, Amandine;Quillien, Veronique
目的：CD90 （Thy-1）是一种糖磷脂酰肌醇锚定糖蛋白，被认为是多种干细胞的替代标志物，包括胶质母细胞瘤（GBM）干细胞（GSC）。然而，CD90的分子和细胞功能尚不清楚。实验设计：利用来自永生化和原代GBM系的细胞模型、体内原位小鼠模型以及与GBM患者MRI特征相关的GBM标本转录组来研究CD90在GBM中的功能。CD90在U251和GBM原代细胞中表达沉默，在CD90阴性的U87细胞中表达补充。结果：我们发现CD90不仅在GSCs上表达，而且在分化程度更高的GBM癌细胞上也表达。在GBM患者中，CD90表达与粘附/迁移基因特征和侵袭性肿瘤特征相关。CD90在GBM细胞中的表达调控显著影响其粘附和迁移特性。此外，原位异种移植物在体内显示CD90表达诱导侵袭性表型。事实上，在我们的GBM细胞模型和GBM患者标本中，CD90的表达导致SRC和FAK信号的增强。药物抑制这些信号节点会减弱cd90阳性细胞的粘附和迁移。值得注意的是，达沙替尼在体内减弱了CD90依赖性GBM细胞的侵袭，并杀死了CD90（高）原代GSC系。结论：我们的数据表明，CD90通过src依赖机制是GBM侵袭性的一个参与者，可以作为CD90高的GBM患者达沙替尼应答的预测因素。(c) 2017 aacr。
Purpose: CD90 (Thy-1) is a glycophosphatidylinositol-anchored glycoprotein considered as a surrogate marker for a variety of stem cells, including glioblastoma (GBM) stem cells (GSC). However, the molecular and cellular functions of CD90 remain unclear.Experimental Design: The function of CD90 in GBM was addressed using cellular models from immortalized and primary GBMlines, in vivo orthotopic mouse models, and GBM specimens' transcriptome associated with MRI features from GBM patients. CD90 expression was silenced in U251 and GBM primary cells and complemented in CD90-negative U87 cells.Results: We showed that CD90 is not only expressed on GSCs but also on more differentiated GBM cancer cells. In GBM patients, CD90 expression was associated with an adhesion/migration gene signature and with invasive tumor features. Modulation of CD90 expression in GBM cells dramatically affected their adhesion and migration properties. Moreover, orthotopic xenografts revealed that CD90 expression induced invasive phenotypes in vivo. Indeed, CD90 expression led to enhanced SRC and FAK signaling in our GBM cellular models and GBM patients' specimens. Pharmacologic inhibition of these signaling nodes blunted adhesion and migration in CD90-positive cells. Remarkably, dasatinib blunted CD90-dependent GBM cell invasion in vivo and killed CD90(high) primary GSC lines.Conclusions: Our data demonstrate that CD90 is an actor of GBM invasiveness through SRC-dependent mechanisms and could be used as a predictive factor for dasatinib response in CD90high GBM patients. (C) 2017 AACR.