CBMT-41. GLIOBLASTOMA CLONES DERIVED FROM TUMOR CORE AND EDGE DISPLAY SPATIAL METABOLIC HETEROGENEITY

The highly heterogeneous nature of glioblastoma (GBM) is a hallmark of limited response to the current therapies and subsequent unfavorable clinical prognosis. Although intratumoral cellular heterogeneity has been recognized in various cancers including GBM, the spatial distributions of tumor-associated cell types and their mechanisms of metabolic pathways that are essential for their heterogeneity remain poorly understood. Here, we utilized the MRI-guided localized biopsy of GBM tumor tissues during surgery, thereby establishing multiple patient-derived GBM clones from both the tumor core and edge tissues in a clonal density, termed core-GBM clones and edge-GBM clones. Using these GBM clones as well as the original tumor tissues, we investigated the underlying molecular mechanisms that drive spatial metabolic heterogeneity in GBM. Comprehensive single cell-metabolome analysis revealed a clear difference between the core and edge clones, as well as between the core and edge tissues. In particular, we noticed metabolic heterogeneity in the nicotinamide adenine dinucleotide (NAD) pathway between the core-GBM clones/tissues and the edge-GBM clones/tissues. Manipulation of the NAD pathway showed distinct phenotypic changes among these clones. These findings suggest that metabolic heterogeneity plays an essential role in therapeutic resistance of glioblastoma.