Recent advances in the genomics of glioblastoma (GBM) led to the introduction of molecular neuropathology but failed to translate into treatment improvement. This is largely attributed to the genetic and phenotypic heterogeneity of GBM, which are considered the major obstacle to GBM therapy. Here, we use advanced human GBM organoid (LEGO: Laboratory Engineered Glioblastoma Organoid) and provide an unprecedented comprehensive characterization of LEGO models using single-cell transcriptome, DNA methylome, metabolome, lipidome, proteome, and phospho-proteome analysis. We discovered that genetic heterogeneity dictates functional heterogeneity across molecular layers and demonstrates that NF1 mutation drives mesenchymal signature. Most importantly, we found that glycerol lipid reprogramming is a hallmark of GBM, and several targets and drugs were discovered along this line. We also provide a genotype-based drug reference map using LEGO based drug screen. This study provides novel human GBM models and a research path toward effective GBM therapy.

中文翻译：

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人类胶质母细胞瘤类器官的多维图谱揭示了高度协调的分子网络和有效药物

胶质母细胞瘤 (GBM) 基因组学的最新进展导致分子神经病理学的引入，但未能转化为治疗改进。这主要归因于 GBM 的遗传和表型异质性，这被认为是 GBM 治疗的主要障碍。在这里，我们使用先进的人类 GBM 类器官（乐高：实验室工程胶质母细胞瘤类器官），并使用单细胞转录组、DNA 甲基化组、代谢组、脂质组、蛋白质组和磷酸化蛋白质组分析对 LEGO 模型进行前所未有的全面表征。我们发现遗传异质性决定了跨分子层的功能异质性，并证明 NF1 突变驱动间充质特征。最重要的是，我们发现甘油脂质重编程是 GBM 的标志，沿着这条线发现了几个目标和药物。我们还使用基于 LEGO 的药物筛选提供基于基因型的药物参考图。本研究提供了新的人类 GBM 模型和有效治疗 GBM 的研究途径。