Spatially resolved chimeric analysis reveals extracellular CKB-mediated ATP uptake at the glioma-astrocyte invasive front

Glioblastoma (GBM) is a highly invasive primary brain tumor that, although rarely metastasizing outside the brain, frequently infiltrates surrounding brain tissue. This infiltrative growth may exploit the brain’s metabolic support system, which involves various brain-resident cells providing essential nutrients and maintaining energy balance. In this study, we investigated the metabolic dependencies of infiltrative GBM cells by combining spatially resolved transcriptomic profiling with advanced computational methods in xenografted GBM models. Our findings reveal that GBM cells upregulate creatine kinase brain type (CKB) at the leading edge to adapt to local energy deprivation. CKB facilitates the conversion of creatine to phosphocreatine, utilizing ATP supplied by astrocytes to support tumor cell survival and invasion. Targeting CKB with cyclocreatine significantly reduced tumor size and restricted infiltrative growth in vivo, indicating that GBM cells utilize CKB to harness extracellular ATP via the creatine pathway. These findings suggest that targeting CKB in GBM may offer a novel therapeutic strategy to combat infiltrative growth in this aggressive cancer. We generated and analyzed spatially resolved RNA profiles in two GBM models: a GSC xenograft model and a TP53, NF1, and PTEN (TNP)-inactivated human neural stem cell-derived model. This approach enabled us to dissect tumor and tumor microenvironment (TME) interactions across spatial contexts.