Tumor-initiating and propagating cells in MYC-driven medulloblastoma

MYC 驱动的髓母细胞瘤中的肿瘤起始和增殖细胞

• 批准号: 9374911
• 负责人: Yanxin Pei
• 金额: $ 21.88万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9374911
• 关键词: Ablation; Animals; Antibodies; Behavior; Biological Assay; Birth; Brain Neoplasms; Cells; Cerebellum; Child; Childhood Malignant Brain Tumor; Data; Diagnosis; Disease; Dominant-Negative Mutation; Embryo; Etiology; Excision; Exhibits; Flow Cytometry; Gene Expression; Genetic Recombination; Hematoxylin and Eosin Staining Method; High Dose Chemotherapy; Histologic; Histology; Human; Immunocompromised Host; Lead; MYC gene; Maintenance; Malignant neoplasm of brain; Mediating; Modeling; Molecular; Molecular Profiling; Monitor; Mus; Mutation; Neonatal; Normal Cell; Operative Surgical Procedures; Patient-Focused Outcomes; Patients; Population; Proliferating; Property; Radiation; Recurrence; Reporting; Resistance; Retroviridae; Rosa; S-Phase Fraction; SHH gene; Staining method; Stains; Stem cells; Subgroup; Survival Rate; TP53 gene; Tamoxifen; Testing; Toxin; Transgenic Mice; Transplantation; Tumor Initiators; Tumor Stem Cells; Ventricular; cancer stem cell; cell type; chemotherapy; conventional therapy; effective therapy; improved outcome; medulloblastoma; mouse model; neoplastic cell; nerve stem cell; novel; novel strategies; outcome forecast; overexpression; postnatal; pregnant; pup; relapse patients; self-renewal; tumor; tumor growth; tumor initiation

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.

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、放疗和大剂量 化疗提高了存活率，许多MB患者仍然死于他们的疾病。因此，新奇和更多 有效的MB治疗方法至关重要。在甲基溴的四个主要分组中，由MYC驱动的(第3组)甲基溴 预后最差，并表现出MYC癌基因的过度表达或扩增；然而， 3MB组仍然难以捉摸。我们最近开发了一种独特的由MYC驱动的MB模型，该模型源于胚胎 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细胞 由于它们具有自我更新和扩散的能力，因此成为转型的目标。SOX2表达已在 胚胎小脑干细胞。因此，我们假设Sox2+细胞是MYC驱动的MB的来源。vt.在.的基础上 转化后，这些细胞可能负责肿瘤的增殖和维持，从而靶向移除这一细胞 人群可能导致肿瘤消退。在这个提案中，我们计划使用我们的老鼠模型来确定(1)是否 (2)SOX2+肿瘤细胞是否为肿瘤细胞-- 增殖细胞(癌症干细胞)；以及(3)是否需要Sox2+肿瘤细胞来维持和切除肿瘤 这些细胞的数量会导致肿瘤消退。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 针对和根除肿瘤细胞的策略，从而改善这种疾病患者的预后。