Glioblastoma cell ability to adapt their functioning to microenvironment changes is a source of the extensive intra-tumor heterogeneity characteristic of this devastating malignant brain tumor. A systemic view of the metabolic pathways underlying glioblastoma cell functioning states is lacking. We analyzed public single cell RNA-sequencing data from glioblastoma surgical resections, which offer the closest available view of tumor cell heterogeneity as encountered at the time of patients' diagnosis. Unsupervised analyses revealed that information dispersed throughout the cell transcript repertoires encoded the identity of each tumor and masked information related to cell functioning states. Data reduction based on an experimentally-defined signature of transcription factors overcame this hurdle. It allowed cell grouping according to their tumorigenic potential, regardless of their tumor of origin. The approach relevance was validated using independent datasets of glioblastoma cell and tissue transcriptomes, patient-derived cell lines and orthotopic xenografts. Overexpression of genes coding for amino acid and lipid metabolism enzymes involved in anti-oxidative, energetic and cell membrane processes characterized cells with high tumorigenic potential. Modeling of their expression network highlighted the very long chain polyunsaturated fatty acid synthesis pathway at the core of the network. Expression of its most downstream enzymatic component, ELOVL2, was associated with worsened patient survival, and required for cell tumorigenic properties in vivo. Our results demonstrate the power of signature-driven analyses of single cell transcriptomes to obtain an integrated view of metabolic pathways at play within the heterogeneous cell landscape of patient tumors.

中文翻译：

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在代谢模块的单细胞水平捕获可区分侵袭性和惰性的胶质母细胞瘤细胞。

胶质母细胞瘤细胞使其功能适应微环境变化的能力是这种毁灭性恶性脑肿瘤广泛的肿瘤内异质性特征的来源。胶质母细胞瘤细胞功能状态的代谢途径缺乏系统的看法。我们分析了来自胶质母细胞瘤手术切除的公共单细胞RNA测序数据，这些数据提供了患者诊断时遇到的肿瘤细胞异质性的最接近可用视图。无监督分析表明，遍布整个细胞转录谱的信息编码了每种肿瘤的身份，并掩盖了与细胞功能状态有关的信息。基于实验定义的转录因子签名的数据减少克服了这一障碍。它允许根据其致瘤潜力对细胞进行分组，而不管其起源的肿瘤如何。使用胶质母细胞瘤细胞和组织转录组，患者来源的细胞系和原位异种移植物的独立数据集验证了方法的相关性。涉及抗氧化，能量和细胞膜过程的编码氨基酸和脂质代谢酶的基因的过表达，表征了具有高致瘤潜力的细胞。他们的表达网络的建模突出了网络核心的非常长的链多不饱和脂肪酸合成途径。其最下游酶促成分ELOVL2的表达与患者生存状况恶化相关，并且是体内细胞致瘤特性所必需的。