Glioblastoma models driven by different mutations converge to the proneural subtype
Glioblastoma models driven by different mutations converge to the proneural subtype
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DOI：
10.1016/j.canlet.2019.11.010
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发表时间：
2020-01-01
期刊：
影响因子：
9.7
通讯作者：
Malatesta, Paolo
中科院分区：
文献类型：
--
作者：
Alessandrini, Francesco;Ceresa, Davide;Malatesta, Paolo
在过去的几十年里，通过在小鼠中复制人类胶质母细胞瘤典型的遗传改变，已经解决了对可靠的胶质瘤同基因动物模型的需求。由于不同的改变是不同分子胶质母细胞瘤亚型的基础，因此通常预期由特定改变诱导的肿瘤代表相应亚型的模型。我们通过多层次分析来验证这一假设，从详细的组织病理学分析到通过微阵列和RNA-seq对由两种不同分子改变诱导的胶质瘤进行的全基因组表达谱分析：PDGF和EGF途径的过度刺激。这些改变分别是前神经和经典胶质母细胞瘤亚型的标志。然而，我们的研究结果一致表明，两个胶质瘤模型之间有很强的相似性。这两种模型的表达谱收敛到一个典型的少突胶质细胞祖细胞的签名，无论起源细胞的广泛分化潜力。基于与人类胶质瘤相似性的分类显示，这两种模型都属于前神经亚型。我们的研究结果强调，再现胶质母细胞瘤亚型的分子改变不一定会产生重现这种亚型的肿瘤模型。
The need of reliable syngeneic animal models for gliomas has been addressed in the last decades by reproducing genetic alterations typical of human glioblastoma in the mouse. Since different alterations underlie different molecular glioblastoma subtypes it is commonly expected that tumors induced by specific alterations represent models of the corresponding subtypes. We tested this assumption by a multilevel analysis ranging from a detailed histopathological analysis to a genome-wide expression profiling by microarray and RNA-seq on gliomas induced by two distinct molecular alterations: the overstimulation of the PDGF- and the EGF- pathways. These alterations are landmarks of proneural and classical glioblastoma subtypes respectively. However, our results consistently showed a strong similarity between the two glioma models. The expression profiles of both models converged toward a signature typical of oligodendrocyte progenitor cells, regardless the wide differentiative potential of the cell of origin. A classification based on similarity with human gliomas profiles revealed that both models belong to the proneural subtype.Our results highlight that reproducing a molecular alteration specific of a glioblastoma subtype not necessarily generates a tumor model recapitulating such subtype.