Glioblastoma (GBM) is increasingly recognized as a disease involving dysfunctional cellular metabolism. GBMs are known to be complex heterogeneous systems containing multiple distinct cell populations and are supported by an aberrant network of blood vessels. A better understanding of GBM metabolism, its variation with respect to the tumor microenvironment, and resulting regional changes in chemical composition is required. This may shed light on the observed heterogeneous drug distribution, which cannot be fully described by limited or uneven disruption of the blood-brain barrier. In this work, we used mass spectrometry imaging (MSI) to map metabolites and lipids in patient-derived xenograft models of GBM. A data analysis workflow revealed that distinctive spectral signatures were detected from different regions of the intracranial tumor model. A series of long-chain acylcarnitines were identified and detected with increased intensity at the tumor edge. A 3D MSI dataset demonstrated that these molecules were observed throughout the entire tumor/normal interface and were not confined to a single plane. mRNA sequencing demonstrated that hallmark genes related to fatty acid metabolism were highly expressed in samples with higher acylcarnitine content. These data suggest that cells in the core and the edge of the tumor undergo different fatty acid metabolism, resulting in different chemical environments within the tumor. This may influence drug distribution through changes in tissue drug affinity or transport and constitute an important consideration for therapeutic strategies in the treatment of GBM. SIGNIFICANCE: GBM tumors exhibit a metabolic gradient that should be taken into consideration when designing therapeutic strategies for treatment.

中文翻译：

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胶质母细胞瘤患者衍生异种移植模型中的局部代谢组学梯度。

胶质母细胞瘤（GBM）越来越多地被认为是一种涉及细胞代谢异常的疾病。众所周知，GBM是复杂的异质系统，包含多个不同的细胞群，并由异常的血管网络支持。需要更好地了解GBM代谢，其相对于肿瘤微环境的变化以及化学成分的区域变化。这可能有助于观察到的异质药物分布，这不能通过血脑屏障的有限或不均匀破坏来充分描述。在这项工作中，我们使用质谱成像（MSI）来绘制GBM患者来源异种移植模型中的代谢物和脂质。数据分析工作流程显示，从颅内肿瘤模型的不同区域检测到了独特的光谱特征。鉴定出一系列长链酰基肉碱，并在肿瘤边缘以增加的强度进行检测。3D MSI数据集表明，在整个肿瘤/正常界面中都观察到了这些分子，并且这些分子并不局限于单个平面。mRNA测序表明，与脂肪酸代谢相关的标志性基因在具有较高酰基肉碱含量的样品中高度表达。这些数据表明，肿瘤核心和边缘的细胞经历不同的脂肪酸代谢，从而导致肿瘤内的化学环境不同。这可能通过改变组织药物亲和力或转运来影响药物分布，并构成GBM治疗策略的重要考虑因素。意义：