Cellular and Molecular Origins of Medulloblastoma Subgroups

在过去10年中，约有750名患有髓母细胞瘤的儿童接受了以联合体为基础的临床试验，估计费用超过1.5亿美元。尽管付出了巨大的努力，但几乎没有产生有意义的分子数据来为下一代临床研究提供信息。因此，所有患者目前都接受同样积极的手术、放射和化疗组合。这种疗法对幸存者造成了毁灭性的副作用，并未能治愈约四分之一的患者。使用基因表达微阵列图谱，我们已经确定了人类髓母细胞瘤的亚群 基因表达、染色体改变、组织学和预后的不同模式。总而言之，这项研究表明，髓母细胞瘤包括几个可能需要不同类型或强度的治疗的亚群；然而，我们仍然缺乏对这些亚群的全面了解，这些亚群是开发新疗法所必需的。我们团队和其他人的工作表明，脑肿瘤的亚群是由癌症干细胞(CSC)产生的，这些细胞共享不同神经前体细胞的基因表达谱，从而能够确定它们的候选起源细胞。我们的初步数据显示，在两个新出现的髓母细胞瘤亚群中，含有Sonic hedgehog通路激活突变的亚群(这里称为SHH-亚群)和β-连环蛋白亚群(CTNNB1-亚群)分别显示出小脑前神经上皮(PCN)内颗粒神经元前体细胞(GNPC)和前体细胞的基因表达谱。这些数据表明，假设：发育中的后脑中不同的祖细胞群体容易获得不同的基因突变，这些突变 将这些转化为CSC。由于这些CSC具有不同的细胞起源和分子特性，因此它们产生的疾病亚群表现出不同的生物学和临床特征。我们将通过专注于髓母细胞瘤的SHH和CTNNB1亚群来检验这一假设：(I)建立有史以来第一个CTNNB1亚群疾病的自发小鼠模型；(Ii)确定SHH和CTNNB1亚群是否由不同类型的CSC及其相关的CSC生态位产生；(Iii)开发经批准的SHH和CTNNB1亚群肿瘤的诊断测试，以选择这些肿瘤的患者进行临床试验。 在一项大型前瞻性临床试验中验证CTNNB1疾病的预后意义。

Over the last 10 years approximately 750 children with medulloblastoma have been treated on consortia-based clinical trials at an estimated cost of over $150 million. Despite this enormous effort, little meaningful molecular data have been generated that will inform the next generation of clinical studies. Consequently, all patients currently receive the same aggressive combination of surgery, radiation and chemotherapy. This treatment inflicts devastating side effects on survivors and fails to cure about one quarter of patients. Using gene expression microarray profiling, we have identified subgroups of human medulloblastoma that display distinct patterns of gene expression, chromosomal alteration, histology and prognosis. The sum of this research suggests that medulloblastoma comprises several subgroups that are likely to require different types or intensities of therapy; however, we still lack the comprehensive understanding of these subgroups necessary to develop new treatments. Work from our group and others has shown that subgroups of brain tumors are generated by cancer stem cells (CSC) that share the gene expression profiles of distinct neural progenitor cells, allowing the identification of their candidate cells-of-origin. Our preliminary data show that two emerging subgroups of medulloblastoma that contain activating mutations in the Sonic hedgehog pathway (from here termed SHH-subgroup) and BETA-CATENIN (CTNNB1-subgroup) display the gene expression profiles of granule neuron precursor cells (GNPC) and precursor cells within the precerebellar neuroepithelium (PCN), respectively. These data suggest the hypothesis that: distinct populations of progenitor cells within the developing hindbrain are predisposed to acquire different gene mutations that transform these into CSC. Since these CSC have distinct cellular origins and molecular properties, then they generate disease subgroups that display different biological and clinical characteristics. We will test this hypothesis by focusing on the SHH and CTNNB1-subgroups of medulloblastoma to: (i) develop the first ever spontaneous mouse model of CTNNB1-subgroup disease; (ii) Determine if SHH and CTNNB1-subgroups are generated by distinct types of CSC and associated CSC niches, (iii) Develop approved diagnostic tests of SHH and CTNNB1-subgroup tumors that can select patients with these tumors for clinical trial, and validate the prognostic significance of CTNNB1- disease in a large prospective clinical trial.