Proteostasis and Cancer Team, INSERM U1242, Chemistry, Oncogenesis Stress Signaling, Université de Rennes 1, Rennes, France.
Centre Eugène Marquis, Rennes, France.
Clin Cancer Res. 2017 Dec 1;23(23):7360-7374. doi: 10.1158/1078-0432.CCR-17-1549. Epub 2017 Sep 22.
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. The function of CD90 in GBM was addressed using cellular models from immortalized and primary GBM lines, 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. 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 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 and killed CD90 primary GSC lines. 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 CD90 GBM patients. .
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，包括神经胶质瘤（GBM）干细胞（GSC）。然而，CD90 的分子和细胞功能仍不清楚。使用来自永生化和原发性 GBM 系、原位小鼠模型以及与 GBM 患者 MRI 特征相关的 GBM 标本转录组的细胞模型来解决 CD90 在 GBM 中的功能。在 U251 和 GBM 原代细胞中沉默 CD90 表达，并在 CD90 阴性的 U87 细胞中补充 CD90。我们表明，CD90 不仅在 GSCs 上表达，而且在更分化的 GBM 癌细胞上表达。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。在 GBM 细胞中调节 CD90 表达极大地影响了它们的粘附和迁移特性。此外，原位异种移植显示 CD90 表达诱导了侵袭表型。事实上，CD90 表达在我们的 GBM 细胞模型和 GBM 患者标本中导致 SRC 和 FAK 信号的增强。这些信号节点的药理学抑制削弱了 CD90 阳性细胞的粘附和迁移。值得注意的是，达沙替尼削弱了依赖 CD90 的 GBM 细胞侵袭，并杀死了 CD90 原代 GSC 系。我们的数据表明，CD90 通过 SRC 依赖性机制成为 GBM 侵袭性的一个因素，并且可以作为 CD90 GBM 患者对达沙替尼反应的预测因子。
