Tumor-initiating and propagating cells in MYC-driven medulloblastoma

项目摘要 髓母细胞瘤是儿童最常见的恶性脑肿瘤。虽然手术放射和高剂量 尽管化疗已经提高了存活率，但许多MB患者仍然死于他们的疾病。因此，小说和更多 MB的有效治疗是至关重要的。在MB的四个主要亚组中，MYC驱动的（第3组）MB 具有最差的预后并表现出MYC癌基因的过度表达或扩增;然而， 第3组MB仍然难以捉摸。我们最近开发了一种独特的MYC驱动的MB模型， 小脑细胞，但肿瘤产生的细胞类型尚不清楚。干细胞一直是最受欢迎的候选人， 由于其自我更新和增殖的能力，它们是转型的目标。Sox 2的表达已经在 胚胎小脑干细胞因此，我们假设Sox 2+细胞作为MYC驱动的MB的起源。后 这些细胞可能负责肿瘤的增殖和维持，因此靶向去除这种细胞。 可能导致肿瘤消退。在这个提议中，我们计划使用我们的小鼠模型来确定（1）是否 正常Sox 2+小脑干细胞是肿瘤起始细胞（起源细胞）;（2）Sox 2+肿瘤细胞是否是肿瘤- 增殖细胞（癌症干细胞）;和（3）肿瘤维持和去除是否需要Sox 2+肿瘤细胞 导致肿瘤消退。通过这些研究的成功完成，我们希望为小说的发展铺平道路。 靶向和根除肿瘤细胞的策略，从而改善这种疾病患者的预后。

Project Summary Medulloblastoma (MB) is the most common malignant brain tumor in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival rates, many MB patients still die from their disease. Thus, novel and more effective therapies for MB are critically important. Among the four major subgroups of MB, MYC-driven (Group 3) MB has the worst prognosis and exhibits overexpression or amplification of the MYC oncogene; however, the etiology of Group 3 MB remains elusive. We recently developed a unique model of MYC-driven MB that originates from embryonic cerebellar cells, but the cell type from which the tumor arises is unclear. Stem cells have been the favored candidates for targets of transformation due to their capacity for self-renewal and proliferation. Sox2 expression has been identified in the embryonic cerebellar stem cells. Thus we hypothesize that Sox2+ cells serve as the origin of MYC-driven MB. Upon transformation, these cells may be responsible for tumor propagation and maintenance, thus targeted removal of this cell population may lead to tumor regression. In this proposal, we plan to use our mouse model to determine (1) whether normal Sox2+ cerebellar stem cells are tumor-initiating cells (cell of origin); (2) whether Sox2+ tumor cells are tumor- propagating cells (cancer stem cells); and (3) whether Sox2+ tumor cells are required for tumor maintenance and removal of these cells results in tumor regression. By successful completion of these studies, we hope to pave the way for novel strategies to target and eradicate tumor cells, thereby improving outcomes for patients with this disease.