165 Astrocyte–Glioblastoma Metabolic Interactions at the Invasive Margin Reveal Therapeutic Vulnerabilities
TL;DR
It is demonstrated that astrocyte–glioblastoma metabolic interactions create targetable dependencies within the tumour microenvironment, and therapeutic targeting of tumour–microenvironment metabolic crosstalk may represent a promising strategy to disrupt tumour adaptation and improve treatment approaches for glioblastoma recurrence.
Abstract
Glioblastoma is an aggressive brain tumour that, despite multimodal treatment, almost always recurs. Infiltrative tumour cells within the brain microenvironment are thought to drive recurrence and are supported by surrounding non-cancerous brain cells. Among these, astrocytes, the most abundant glial cells in the brain, play key roles in regulating metabolic homeostasis. The metabolic dependencies underpinning astrocyte–glioblastoma interactions remain poorly defined. Identifying targetable metabolic pathways within this niche may inform new therapeutic strategies. Patient-derived glioblastoma invasive margin cells and human cortical astrocytes were cultured individually and in co-culture to model tumour–microenvironment interactions. Single-cell metabolic profiling was performed using microscopy-guided atmospheric pressure matrix-assisted laser desorption/ionisation (AP-MALDI) imaging mass spectrometry at 10 μm spatial resolution. Complementary liquid chromatography–mass spectrometry enabled pathway-level analysis. Stable isotope tracing using labelled metabolic precursors was then used to investigate metabolite utilisation and intercellular exchange in selected pathways. Pharmacological inhibitors targeting amino acid transport and metabolism were applied to assess therapeutic relevance. Glioblastoma invasive margin cells cultured with astrocytes showed distinct metabolic adaptations, including changes in amino acids and lipid metabolism consistent with microenvironment-driven metabolic reprogramming. Stable isotope tracing demonstrated engagement of tyrosine and phenylalanine pathways, supporting metabolic exchange and pathway utilisation within the tumour–astrocyte microenvironment. Pharmacological targeting of amino acid transport and downstream metabolic processes resulted in differential functional responses. These findings demonstrate that astrocyte–glioblastoma metabolic interactions create targetable dependencies within the tumour microenvironment. Therapeutic targeting of tumour–microenvironment metabolic crosstalk may represent a promising strategy to disrupt tumour adaptation and improve treatment approaches for glioblastoma recurrence.