Glioma stem cells (GSCs) have been implicated in the promotion of malignant progression. Epidermal growth factor receptor variant (EGFRv) has been associated with glioma “stemness”. However, the molecular mechanism is not clear. In this study, we were committed to investigate the role of EGFRv in GSCs and presented a new therapeutic target in EGFRvIII positive GSCs. The results showed that EGFRvIII could induce the expression of p-Src and PLK1, and both could induce the Notch1-SOX2 signaling pathway to promote self-renewal and tumor progression of GSCs. Mechanistically, both p-Src and PLK1 can induce Notch1, and the intracellular domain of Notch1 (NICD) can directly bind to SOX2, thereby promoting the maintenance of glioma stem cells. Furthermore, Saracatinib (Src inhibition) and BI2536 (PLK1 inhibition) diminished GSC self-renewal in vitro, and combining the two inhibitors increased survival of orthotopic tumor-bearing mice. Taken together, these data indicate that p-Src and PLK1 contribute to cancer stemness in EGFRvIII-positive GSCs by driving Notch1-SOX2 signaling, a finding that has important clinical implications.

神经胶质瘤干细胞（GSC）与促进恶性进展有关。表皮生长因子受体变异体（EGFRv）与神经胶质瘤的“干性”有关。然而，其分子机制尚不清楚。在本研究中，我们致力于研究 EGFRv 在 GSC 中的作用，并提出了 EGFRvIII 阳性 GSC 的新治疗靶点。结果表明，EGFRvIII可诱导p-Src和PLK1的表达，两者均能诱导Notch1-SOX2信号通路促进GSC的自我更新和肿瘤进展。从机制上讲，p-Src和PLK1都可以诱导Notch1，Notch1的胞内结构域（NICD）可以直接与SOX2结合，从而促进胶质瘤干细胞的维持。此外，Saracatinib（Src 抑制）和 BI2536（PLK1 抑制）在体外可减少 GSC 自我更新，两种抑制剂的组合可增加原位肿瘤小鼠的存活率。总而言之，这些数据表明 p-Src 和 PLK1 通过驱动 Notch1-SOX2 信号传导，促进 EGFRvIII 阳性 GSC 的癌症干细胞性，这一发现具有重要的临床意义。