Elimination of dormant cancer stem cells by disrupting glucocorticoid mediated lipid metabolism in glioblastoma [shRNA KD]

Little progress has been made in therapeutic treatment of glioblastoma (GBM) in the last decade despite rapid progress in molecular understanding of brain tumors. Targeting cancer stem cells was considered as a strategy to treat GBM. Here we show that the stress hormone glucocorticoid is essential for the maintenance of brain tumor stem cells (BTSCs), which are resistant to conventional therapy. The glucocorticoid receptor (GR) regulates metabolic plasticity and chemoresistance of the dormant BTSC via controlling expression of GPD1 (glycerol-3-phosphate dehydrogenase 1), which is an essential regulator of lipid metabolism in BTSCs. Genomic, lipidomic and cellular analysis confirm that GR/GPD1 regulation is essential for BTSCs metabolic plasticity and survival. We further demonstrate that the GR agonist dexamethasone (DEXA), which is commonly used to treat GBM edema, abolishes the effect of chemotherapy drug temozolomide (TMZ) by upregulating GPD1 and thus promoting tumor cell dormancy and TMZ resistance, this provides a mechanistic explanation and thus settle the debate of steroid usage in brain tumor patient edema control. Pharmacological inhibition of GR/GPD1 pathway disrupts metabolic plasticity, induces ferroptosis and immune activation thus prolongs animal survival, which is superior to standard chemotherapy. This study identifies an important mechanism regulating cancer stem cell dormancy and provides a new opportunity for GBM treatment.