Glioblastoma Models Reveal the Connection between Adult Glial Progenitors and the Proneural Phenotype

BackgroundTumor heterogeneity is a major obstacle for finding effective treatment of Glioblastoma (GBM). Based on global expression analysis, GBM can be classified into distinct subtypes: Proneural, Neural, Classical and Mesenchymal. The signatures of these different tumor subtypes may reflect the phenotypes of cells giving rise to them. However, the experimental evidence connecting any specific subtype of GBM to particular cells of origin is lacking. In addition, it is unclear how different genetic alterations interact with cells of origin in determining tumor heterogeneity. This issue cannot be addressed by studying end-stage human tumors. Methodology/Principal FindingsTo address this issue, we used retroviruses to deliver transforming genetic lesions to glial progenitors in adult mouse brain. We compared the resulting tumors to human GBM. We found that different initiating genetic lesions gave rise to tumors with different growth rates. However all mouse tumors closely resembled the human Proneural GBM. Comparative analysis of these mouse tumors allowed us to identify a set of genes whose expression in humans with Proneural GBM correlates with survival. Conclusions/SignificanceThis study offers insights into the relationship between adult glial progenitors and Proneural GBM, and allows us to identify molecular alterations that lead to more aggressive tumor growth. In addition, we present a new preclinical model that can be used to test treatments directed at a specific type of GBM in future studies.研究背景 肿瘤异质性是研发胶质母细胞瘤（Glioblastoma, GBM）有效治疗方案的主要障碍。基于全局基因表达分析，胶质母细胞瘤可分为四类独立亚型：前神经元型（Proneural）、神经元型（Neural）、经典型（Classical）以及间充质型（Mesenchymal）。这些不同肿瘤亚型的特征或可反映其起源细胞的表型。然而，目前仍缺乏将任意特定胶质母细胞瘤亚型与特定起源细胞相关联的实验证据。此外，尚不明确不同遗传改变与起源细胞如何相互作用，共同调控肿瘤异质性的形成。仅通过研究终末期人类肿瘤，无法解决这一问题。 研究方法与主要结果 为解决该问题，本研究利用逆转录病毒向成年小鼠脑内的胶质祖细胞递送致瘤性遗传损伤。将诱导生成的小鼠肿瘤与人胶质母细胞瘤进行对比分析后发现，不同的起始遗传损伤可诱导生成生长速率各异的肿瘤，但所有小鼠肿瘤均与人前神经元型胶质母细胞瘤高度相似。通过对这些小鼠肿瘤的比较分析，我们鉴定出一组基因，其在人前神经元型胶质母细胞瘤患者中的表达水平与患者生存率相关。 研究结论与意义 本研究揭示了成年胶质祖细胞与前神经元型胶质母细胞瘤之间的关联，并鉴定出可导致肿瘤侵袭性增强的分子改变。此外，本研究构建了一种全新的临床前模型，未来可用于测试针对特定亚型胶质母细胞瘤的治疗方案。