Migration of human glioma cells (hGCs) within the brain parenchyma makes glioblastoma one of the most aggressive and lethal tumors. Studies of the cellular and molecular mechanisms underlying hGC migration are hindered by the limitations of existing glioma models. Here we developed a dorsal root ganglion axon-oligodendrocyte-hGC co-culture to study in real time the migration and interaction of hGCs with their microenvironment. hGCs interact with myelinated and non-myelinated axons through the formation of pseudopodia. Isolation of pseudopodia-localized polysome-bound RNA reveals transcripts of Lck, Paxillin, Crk-II, and Rac1 that undergo local translation. Inhibition of Lck phosphorylation using a small-molecule inhibitor (Lck-I), blocks the phosphorylation of Paxillin and Crk-II, the formation of pseudopodia and the migration of hGCs. In vivo intraventricular administration of the Lck-I using an orthotopic xenograft glioma model, results in statistically significant inhibition of tumor size and significant down-regulation of Nanog-targeted genes, which are associated with glioblastoma patient survival. Moreover, treatment of human glioma stem cells (hGSCs) with Lck-I, results in significant inhibition of self-renewal and tumor-sphere formation. The involvement of Lck in different levels of glioma malignant progression, such as migration, tumor growth, and regulation of cancer stemness, makes Lck a potentially important therapeutic target for human glioblastomas.

中文翻译：

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使用Lck靶向抑制剂调节人类神经胶质瘤细胞迁移，肿瘤生长和干基因表达。

人脑神经胶质瘤细胞（hGCs）在脑实质内的迁移使胶质母细胞瘤成为最具攻击性和致命性的肿瘤之一。现有的神经胶质瘤模型的局限性阻碍了对hGC迁移的细胞和分子机制的研究。在这里，我们开发了背根神经节轴突-少突胶质细胞-hGC共培养，以实时研究hGC与其微环境的迁移和相互作用。hGC通过假足的形成与有髓和无髓轴突相互作用。伪足定位的多核糖体结合的RNA的分离揭示了Lck，Paxillin，Crk-II和Rac1的转录本，这些转录本经过了局部翻译。使用小分子抑制剂（Lck-I）抑制Lck磷酸化可阻止Paxillin和Crk-II的磷酸化，假足的形成和hGC的迁移。使用原位异种移植神经胶质瘤模型在体内进行Lck-1的脑室内给药，会在统计学上显着抑制肿瘤大小，并显着下调Nanog靶向基因，这与胶质母细胞瘤患者的生存有关。而且，用Lck-1治疗人神经胶质瘤干细胞（hGSC）导致显着抑制自我更新和肿瘤球形成。Lck参与不同水平的神经胶质瘤恶性进展，例如迁移，肿瘤生长和癌症干性的调节，使得Lck成为人胶质母细胞瘤的潜在重要治疗靶标。与胶质母细胞瘤患者的生存有关。而且，用Lck-1治疗人神经胶质瘤干细胞（hGSC）导致显着抑制自我更新和肿瘤球形成。Lck参与不同水平的神经胶质瘤恶性进展，例如迁移，肿瘤生长和癌症干性的调节，使得Lck成为人胶质母细胞瘤的潜在重要治疗靶标。与胶质母细胞瘤患者的生存有关。而且，用Lck-1治疗人神经胶质瘤干细胞（hGSC）导致显着抑制自我更新和肿瘤球形成。Lck参与不同水平的神经胶质瘤恶性进展，例如迁移，肿瘤生长和癌症干性的调节，使得Lck成为人胶质母细胞瘤的潜在重要治疗靶标。