Radiation Oncology, Beaumont Health, Royal Oak, Michigan.
Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
Neuro Oncol. 2019 Feb 19;21(3):337-347. doi: 10.1093/neuonc/noy185.
Although considerable progress has been made in understanding molecular alterations driving gliomagenesis, the diverse metabolic programs contributing to the aggressive phenotype of glioblastoma remain unclear. The aim of this study was to define and provide molecular context to metabolic reprogramming driving gliomagenesis.
Integrative cross-platform analyses coupling global metabolomic profiling with genomics in patient-derived glioma (low-grade astrocytoma [LGA; n = 28] and glioblastoma [n = 80]) were performed. Identified programs were then metabolomically, genomically, and functionally evaluated in preclinical models.
Clear metabolic programs were identified differentiating LGA from glioblastoma, with aberrant lipid, peptide, and amino acid metabolism representing dominant metabolic nodes associated with malignant transformation. Although the metabolomic profiles of glioblastoma and LGA appeared mutually exclusive, considerable metabolic heterogeneity was observed in glioblastoma. Surprisingly, integrative analyses demonstrated that O6-methylguanine-DNA methyltransferase methylation and isocitrate dehydrogenase mutation status were equally distributed among glioblastoma metabolic profiles. Transcriptional subtypes, on the other hand, tightly clustered by their metabolomic signature, with proneural and mesenchymal tumor profiles being mutually exclusive. Integrating these metabolic phenotypes with gene expression analyses uncovered tightly orchestrated and highly redundant transcriptional programs designed to support the observed metabolic programs by actively importing these biochemical substrates from the microenvironment, contributing to a state of enhanced metabolic heterotrophy. These findings were metabolomically, genomically, and functionally recapitulated in preclinical models.
Despite disparate molecular pathways driving the progression of glioblastoma, metabolic programs designed to maintain its aggressive phenotype remain conserved. This contributes to a state of enhanced metabolic heterotrophy supporting survival in diverse microenvironments implicit in this malignancy.
尽管在理解驱动神经胶质瘤发生的分子改变方面已经取得了相当大的进展，但导致胶质母细胞瘤侵袭性表型的不同代谢程序仍不清楚。本研究旨在定义并提供分子背景，以了解驱动神经胶质瘤发生的代谢重编程。
对患者来源的神经胶质瘤（低级别星形细胞瘤[LGA；n=28]和胶质母细胞瘤[n=80]）进行了整合的跨平台分析，将全局代谢组学分析与基因组学相结合。然后在临床前模型中对鉴定出的程序进行代谢组学、基因组学和功能评估。
明确的代谢程序区分了 LGA 和胶质母细胞瘤，异常的脂质、肽和氨基酸代谢代表了与恶性转化相关的主要代谢节点。尽管胶质母细胞瘤和 LGA 的代谢组学图谱似乎相互排斥，但在胶质母细胞瘤中观察到相当大的代谢异质性。令人惊讶的是，整合分析表明 O6-甲基鸟嘌呤-DNA 甲基转移酶甲基化和异柠檬酸脱氢酶突变状态在胶质母细胞瘤的代谢图谱中分布均匀。另一方面，转录亚型则根据其代谢特征紧密聚类，神经前体细胞和间充质肿瘤的特征相互排斥。将这些代谢表型与基因表达分析相结合，揭示了精心协调和高度冗余的转录程序，这些程序通过从微环境中主动摄取这些生化底物来支持观察到的代谢程序，从而导致增强的代谢异养状态。这些发现通过代谢组学、基因组学和功能在临床前模型中得到了再现。
尽管驱动胶质母细胞瘤进展的分子途径不同，但旨在维持其侵袭性表型的代谢程序仍然保守。这导致了增强的代谢异养状态，支持了这种恶性肿瘤中不同微环境中的生存。
