76 Metabolic Heterogeneity in Brain Tumours: Distinguishing Brain Metastases from Glioblastomas

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Abstract Introduction Brain metastases account for nearly 20% of cancer-related deaths and have a five-year survival rate of 2.4%, most commonly arising from breast and lung cancers. Despite therapeutic advances, prognosis remains poor, highlighting the need for novel treatment strategies. Metabolic reprogramming is a hallmark of cancer, reflecting the ability of malignant cells to remodel metabolic pathways to support invasion, proliferation, and survival. The brain microenvironment is metabolically distinct, characterized by restricted nutrient availability, high neuronal activity, and a tightly regulated blood-brain barrier. Tumour cells metastasizing from extracranial sites must therefore undergo metabolic adaptation to colonize and proliferate within the brain. This study investigates metabolic differences between brain metastases and primary brain tumours to identify adaptive metabolic pathways with therapeutic potential. Methods Steady-state metabolic profiling was performed on fresh-frozen tumour tissues from patients undergoing surgical resection for glioblastoma(GBM), breast and lung cancer brain metastases at Queen Elizabeth Hospital, Birmingham. Findings were validated in patient-derived 2D cell models and ex vivo tumour slices using 13C6-glucose and 13C6-palmitate isotope tracing to assess pathway utilisation. Polar metabolites were analysed using LC-MS, and non-polar metabolites using GC-MS. Results Breast cancer brain metastases exhibited elevated free fatty acids relative to GBM, indicating increased de-novo lipogenesis to support membrane biosynthesis, energy production, and tumour growth within lipid-restricted brain environment. This was supported by increased FASN and ACC1 expression and PLIN2 staining for lipid droplets. In contrast, lung cancer brain metastases showed elevated GABA and glutamine levels, suggesting metabolic adaptation through neuronal/glial pathways and utilisation of neurotransmitter-linked substrates. Conclusion Brain metastases exhibit tumour-type specific metabolic reprogramming to adapt to the brain microenvironment highlighting distinct metabolic survival strategies compared to GBM, and supporting the need for tumour-specific treatment strategies.

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