CD133蛋白的C端剪切：胶质瘤干细胞动态和静态转换的分子开关

Cancer Stem Cells (CSCs) are localized in a microenvironment known as the stem cell "niche" where they are not only maintained in an quiescent state to evade drug treatment, but also start self-renewal to keep the expansion of tumor . It's the key point to explore the mechanism of switch between quiescent and proliferation in CSCs research. CD133/Prominin 1, a widely used marker of cancer stem cells and progenitor cells, plays a critical role in proliferation, invasion and chemotherapy resistance in the process of tumor development. However, the molecular mechanisms of how CD133 interacts with the microenvironment are not well studied. Our previous study found that CD133 positive single cells had a significantly higher proliferative capacity compared to CD133 positive cells in the "aggregation island" in glioma tissure. A further research found that CD133 triggered self-renewal of glioma stem cell through its C-terminal cleavage by ADMA17/TACE when cells were in a sparse state. Increasing cell number leads to trans-interactions of CD133 between plasma membrane of the opposing cells, which prevent the cleavage of CD133. This study will illuminate that CD133 functions as a cell density-sensor on the membrane protrusions to count cell number, and triggers self-renewal of glioma stem cells through its C-terminal cleavage, indicating that targeting CD133 cleavage in cancers may be of clinical value.

肿瘤干细胞既要保持相对静止以逃避药物治疗，又要启动自我更新以形成肿瘤， 解析这种动、静态转换的机制是阐释肿瘤形成的关键问题之一。肿瘤干细胞标志物CD133调控肿瘤干细胞的增殖、侵袭和耐药，但CD133如何与外界环境的交流仍然是"盲点"。我们前期研究发现CD133阳性胶质瘤干细胞在孤立分布时比聚集时具有更强的增殖能力。深入研究发现孤立胶质瘤干细胞膜表面的CD133的C端被ADAM17酶剪切，剪切体促进胶质瘤干细胞自我更新；胶质瘤干细胞增多后，相邻细胞表面的CD133反式相互作用，抑制剪切，从而维持相对静止状态。本项目拟利用人胶质瘤标本和小鼠胶质瘤原位模型，通过研究CD133蛋白C端剪切的机制、功能和如何受细胞密度调控，阐释胶质瘤干细胞通过感受数量调控自身状态转换的机制。首次证实CD133是胶质瘤干细胞的"计数器"，从而为胶质瘤干细胞与微环境的互动研究和肿瘤的治疗提供思路。

肿瘤干细胞既要保持相对静止以逃避药物治疗，又要启动自我更新以形成肿瘤， 解析这种动、静态转换的机制是阐释肿瘤形成的关键问题之一。肿瘤干细胞标志物CD133调控肿瘤干细胞的增殖、侵袭和耐药，但CD133如何与外界环境的交流仍然是“盲点”。本项目研究发现CD133阳性胶质瘤干细胞在孤立分布时比聚集时具有更强的增殖能力。孤立胶质瘤干细胞膜表面的CD133的C端被ADAM17酶剪切，剪切体促进胶质瘤干细胞自我更新；胶质瘤干细胞增多后，相邻细胞表面的CD133反式相互作用，抑制剪切，从而维持相对静止状态。并且发现CD133的C端可以和p85相互作用、和Src相互作用促进肿瘤干细胞自我更新、肿瘤细胞侵袭等。本项目通过近4年的研究阐释胶质瘤干细胞通过感受数量调控自身状态转换的机制。相关研究发表于J Biol Chem、PNAS、Oncotarget等杂志。并申请1项专利。在全国糖生物学会议多次介绍。