GPD1 Specifically Marks Dormant Glioma Stem Cells with a Distinct Metabolic Profile

Brain tumor stem cells (BTSCs) are a chemoresistant population that can drive tumor growth and relapse, but the lack of BTSC-specific markers prevents selective targeting that spares resident stem cells. Through a ribosome-profiling analysis of mouse neural stem cells (NSCs) and BTSCs, we find glycerol-3-phosphate dehydrogenase 1 (GPD1) expression specifically in BTSCs and not in NSCs. GPD1 expression is present in the dormant BTSC population, which is enriched at tumor borders and drives tumor relapse after chemotherapy. GPD1 inhibition prolongs survival in mouse models of glioblastoma in part through altering cellular metabolism and protein translation, compromising BTSC maintenance. Metabolomic and lipidomic analyses confirm that GPD1+ BTSCs have a profile distinct from that of NSCs, which is dependent on GPD1 expression. Similar GPD1 expression patterns and prognostic associations are observed in human gliomas. This study provides an attractive therapeutic target for treating brain tumors and new insights into mechanisms regulating BTSC dormancy. [Display omitted] •GPD1 is expressed in brain tumor stem cells (BTSCs) but not normal neural stem cells•GPD1+ BTSCs are dormant but induced to divide by chemotherapy•GPD1 inhibition blocks BTSC maintenance and prolongs survival•GPD1 regulates essential metabolic and molecular programs in glioblastoma Identifying markers specifically expressed by brain tumor stem cells (BTSCs) may enable specific therapies that spare their normal tissue-resident counterparts. Rusu et al. identify GPD1 as a specific marker for dormant and chemoresistant BTSCs and show that targeting GPD1 disrupts BTSC maintenance and extends survival.