FoxD1在间质型脑胶质瘤干细胞替莫唑胺耐药中的作用及机制研究

Glioma stem cells (GSCs) are a small fraction of a subpopulation of cells in the bulk tumor that possess the capacity to self-renew and maintain tumor-initiating capacity, which are considered as the roots of radio- or chemo-resistance and tumor recurrence. Temozolomide (TMZ) is currently used as first-line therapy for the treatment of glioblastoma (GBM). However, the emergence of drug resistance is a key determinant of treatment failure. Recent studies have demonstrated that forkhead box D1 (FoxD1) is frequently overexpressed in mesenchymal subtype of GSCs. However, the role and function of FoxD1 in GSCs need to be elucidated. Based on our previous microarray data from GBM patients, we observed that FoxD1 is upregulated in primary GBM cell lines and tumor tissues upon TMZ treatment, suggesting a possible role of FoxD1 in the acquisition of TMZ resistance. To test this hypothesis, we planned to generate the different subtypes of GSCs by isolating neurosphere-forming cells from freshly resected specimens of human GBM, and establish TMZ-resistant GSC-derived intracranial xenograft mouse models, and investigate the effects of FoxD1-mediated signaling on TMZ resistance. This project provides new insight into the mechanism of TMZ resistance and its reversal in GBM.

胶质瘤干细胞（Glioma stem cell，GSC）是一小群具有干细胞特性的肿瘤克隆源性细胞。GSC能凭借其自我更新的能力和处于静止期的特性，逃脱放射线和药物的杀伤作用，继而导致肿瘤在放化疗后复发。替莫唑胺（TMZ）是目前国际上推荐的胶质瘤母细胞瘤(GBM)一线化疗药物，但化疗过程中耐药的产生是导致治疗失败的重要原因之一。最近的研究表明叉头框蛋白D1（FoxD1）在间质型GBM及间质型GSC中表达水平显著异常。申请人通过对前期工作基因芯片进行筛选，发现FoxD1在TMZ耐药GBM原代细胞中表达明显升高，提示FoxD1可能在TMZ化疗耐药中发挥重要作用。为验证这一假说，本课题拟通过分离筛选神经前体型以及间质型GSC、建立裸鼠颅内GSC移植瘤耐药模型, 从分子、细胞、组织以及动物整体水平等多层次探讨FoxD1及其下游通路对TMZ耐药性的影响。本研究为逆转TMZ获得性耐药提供新的思路和方法。