肿瘤干细胞目前已在多种癌症中发现，并证实参与肿瘤发生、发展、耐药与复发，故如何调控和诱导肿瘤干细胞分化，降低耐药已成为针对肿瘤干细胞靶向治疗中的关键科学问题之一。申请人发在Molecular Cancer与Stem Cells杂志上的研究结果表明CD133+胶质瘤干细胞参与耐药。本课题组前期实验发现：1）骨分化相关基因Nell-1在胶质瘤组织中低表达或不表达；2）在胶质瘤干细胞中过表达Nell-1，促进干细胞分化，降低CD133表达并提高对化疗药物的敏感性，提示Nell-1可能参与肿瘤干细胞分化，但调控功能与分子机制需深入探索。为此，在前期基础上项目拟用过表达、RNAi、组织芯片、FACS、活体成像等技术从分子、细胞与动物水平研究Nell-1诱导肿瘤干细胞分化的功能及临床意义，阐明Nell-1调控肿瘤干细胞分化的分子机制，为今后临床上开展肿瘤干细胞靶向分化治疗提供依据。

Cancer stem cells have recently been identified in many types of cancer and has been found to play an important role in cancer initiation, development ，drug resistance and recurrence. To uncover the mechanisms by which cancer stem cells sustain their stemness and know how to induce them differentiation and decrease drug resistance has become a critical scientific issue in attempts to develop a therapy to induce cancer stem cell differentiation and reverse their drug resistance. In our previous studies published in Molecular Cancer and Stem Cells, we demonstrated that CD133-positive cancer stem cells derived from malignant glioma present significant resistance to chemotherapy.Our recent pilot study found that Nell-1, a novel growth factor believed to promote osteoblast differentiation，is not expressed or exhibits a very low expression in malignant glioma tissue. We also found that over-expressing Nell-1 by plasmid transfection on glioma cancer stem cells induces differentiation, decreases CD133 expression and increase its sensitivity to chemotherapy drugs, which suggests Nell-1 plays a crucial role in cancer stem cell differentiation and decrease of its drug resistance, although further investigation is required to determine the mechanism involved. Based on our previous results, in this project we will explore the molecular mechanism and clarify the related signal pathway by which Nell-1 induces cancer stem cell differentiation and effects of drug resistance through a series of experiments, including studies using an in vivo animal model, as well as in vitro cell biology and molecular expression analysis using overexpression, RNAi, tissue array, FACS and living imaging technology. Our study should provide evidence to further understanding of the molecular mechanisms by which Nell-1 induces cancer stem cell differentiation, decreases drug resistance. Our goal is to contribute to the development of a novel therapy that can selectively target cancer stem cells.