The invasive behavior of glioblastoma, the most aggressive primary brain tumor, is considered highly relevant for tumor recurrence. However, the invasion zone is difficult to visualize by Magnetic Resonance Imaging (MRI) and is protected by the blood brain barrier, posing a particular challenge for treatment. We report biological features of invasive growth accompanying tumor progression and invasion based on associated metabolic and transcriptomic changes observed in patient derived orthotopic xenografts (PDOX) in the mouse and the corresponding patients’ tumors. The evolution of metabolic changes, followed in vivo longitudinally by 1H Magnetic Resonance Spectroscopy (1H MRS) at ultra-high field, reflected growth and the invasive properties of the human glioblastoma transplanted into the brains of mice (PDOX). Comparison of MRS derived metabolite signatures, reflecting temporal changes of tumor development and invasion in PDOX, revealed high similarity to spatial metabolite signatures of combined multi-voxel MRS analyses sampled across different areas of the patients’ tumors. Pathway analyses of the transcriptome associated with the metabolite profiles of the PDOX, identified molecular signatures of invasion, comprising extracellular matrix degradation and reorganization, growth factor binding, and vascular remodeling. Specific analysis of expression signatures from the invaded mouse brain, revealed extent of invasion dependent induction of immune response, recapitulating respective signatures observed in glioblastoma. Integrating metabolic profiles and gene expression of highly invasive PDOX provided insights into progression and invasion associated mechanisms of extracellular matrix remodeling that is essential for cell–cell communication and regulation of cellular processes. Structural changes and biochemical properties of the extracellular matrix are of importance for the biological behavior of tumors and may be druggable. Ultra-high field MRS reveals to be suitable for in vivo monitoring of progression in the non-enhancing infiltration zone of glioblastoma.

中文翻译：

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通过患者与小鼠相应原位异种移植物之间的比较揭示胶质母细胞瘤侵袭的代谢和转录组学特征

胶质母细胞瘤是最具侵袭性的原发性脑肿瘤，其侵袭行为被认为与肿瘤复发高度相关。然而，侵入区很难通过磁共振成像 (MRI) 可视化，并且受到血脑屏障的保护，对治疗提出了特殊的挑战。我们根据在小鼠和相应患者肿瘤中观察到的患者衍生的原位异种移植物 (PDOX) 中观察到的相关代谢和转录组学变化报告了伴随肿瘤进展和侵袭的侵袭性生长的生物学特征。代谢变化的演变，以及在体内纵向跟踪的超高场 1H 磁共振光谱 (1H MRS)，反映了移植到小鼠大脑 (PDOX) 中的人类胶质母细胞瘤的生长和侵袭特性。MRS 衍生代谢物特征的比较反映了 PDOX 中肿瘤发展和侵袭的时间变化，揭示了与在患者肿瘤不同区域采样的组合多体素 MRS 分析的空间代谢物特征高度相似。对与 PDOX 代谢物谱相关的转录组进行通路分析，确定了侵袭的分子特征，包括细胞外基质降解和重组、生长因子结合和血管重塑。对来自被入侵小鼠大脑的表达特征进行特定分析，揭示了免疫反应的入侵依赖性诱导程度，概括了在胶质母细胞瘤中观察到的各个特征。整合高侵袭性 PDOX 的代谢谱和基因表达提供了对细胞外基质重塑的进展和侵袭相关机制的见解，这对于细胞间通讯和细胞过程的调节至关重要。细胞外基质的结构变化和生化特性对肿瘤的生物学行为很重要，并且可能是可药用的。超高场 MRS 显示适用于体内监测胶质母细胞瘤非增强浸润区的进展。