恶性胶质瘤（MG）的侵袭性是其成功治疗的主要障碍。前期研究发现，集群运动是MG细胞在脑白质中的新迁移形式。我们提出：MG细胞的集群迁移可维持肿瘤干细胞表型，促进肿瘤细胞趋化引导，增强侵袭迁移能力。本项目拟对人脑MG白质浸润区和鼠脑MG胼胝体侵袭区存在的集群细胞进行干细胞小生境确定，研究集群细胞的Notch通路活性和侵袭能力；分析组织切片和体外实验中Notch配体/受体与nestin、SDF-1/CXCR4以及Notch配体/受体和Arp2/3复合物、hMena的表达特征；通过改良的transwell实验，研究细胞集群状态促进细胞趋化引导的机理；利用体外实验平台，研究激活的Notch通路经CXCR4对PI3K/Akt/mTOR通路的上调作用，以及集群细胞侵袭迁移能力的增强；通过Notch通路和PI3K/Akt/mTOR通路联合靶向抑制实验，为MG抗侵袭治疗提供新思路。

One of the major obstacles to the successful treatment of malignant glioma is their highly infiltrative property. In our previous study, we found a new type of glioma cell migration - collective cell motility. We hypothesize that collective cell motility would maintain the phenotype of glioma stem cells, promote chemotactic guidance and intercellular guidance, and enhance the ability of cell invasion and migration. In this study, we intend to identify glioma stem cell niches among clusters of collective cells in infiltrative zone of human malignant glioma in white matter and invaded corpus callosum in rat intracranial glioma model. We will investigate activation of Notch signaling pathway and the ability of cell invasion and migration, analyze expression characteristics among Notch ligand/receptor, nestin and SDF-1/CXCR4 as well as among Notch ligand/receptor,Arp2/3 comples and hMena. We will also investigate guidance mechanism in collective cell structure by an improved transwell assay. Using an established experimental platform in vitro, we will survey how activated Notch signaling pathway upregulates the PI3K/Akt/mTOR signaling pathway via CXCR4 and enhances invasion and migration ability of collective cells. A combined therapies targeting to inhibit both Notch signaling pathway and PI3K/Akt/mTOR signaling pathway in this study would supply new clues for anti-invasion therapy for malignant glioma.