Similar Datasets
Project description: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.
2025-10-05 | GSE215242 | GEO
Project description: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.
2025-10-05 | GSE214858 | GEO
Project description: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.
2025-10-05 | GSE215243 | GEO
Project description:Elimination of dormant cancer stem cells by disrupting glucocorticoid mediated lipid metabolism in glioblastoma
| PRJNA889416 | ENA
Project description:Elimination of dormant cancer stem cells by disrupting glucocorticoid mediated lipid metabolism in glioblastoma I
| PRJNA887406 | ENA
Project description:Elimination of dormant cancer stem cells by disrupting glucocorticoid mediated lipid metabolism in glioblastoma [treatment]
| PRJNA889414 | ENA
Project description:Elimination of dormant cancer stem cells by disrupting glucocorticoid mediated lipid metabolism in glioblastoma [shRNA KD]
| PRJNA889415 | ENA
Project description:Glioblastoma (GBM) is a highly aggressive form of brain tumor characterized by dysregulated metabolism. Increased fatty acid oxidation (FAO) protects tumor cells from lipid peroxidation-induced cell death, although the precise mechanisms involved remain unclear. Herein, we report that loss of tumor necrosis factor receptor-associated factor 3 (TRAF3) in GBM critically regulates lipid peroxidation and tumorigenesis by controlling the oxidation of polyunsaturated fatty acids (PUFAs). TRAF3 is frequently repressed in GBM due to promoter hypermethylation. TRAF3 interacts with enoyl-CoA hydratase 1 (ECH1), an enzyme catalyzing the isomerization of unsaturated fatty acids (UFAs), and mediates K63-linked ubiquitination of ECH1 at Lys214. ECH1 ubiquitination impedes TOMM20-dependent mitochondrial translocation of ECH1, which otherwise promotes the oxidation of UFAs, preferentially the PUFAs, and limits lipid peroxidation. Overexpression of TRAF3 enhances the sensitivity of GBM to ferroptosis and anti-PD-L1 immunotherapy in mice. Thus, the TRAF3-ECH1 axis plays a key role in the metabolism of PUFAs, and is crucial for lipid peroxidation damage and immune elimination in GBM.
2025-03-11 | GSE285922 | GEO
Project description:BackgroundCancer stem cells (CSCs) are considered as the major cause to tumor initiation, recurrence, metastasis, and drug resistance, driving poor clinical outcomes in patients. Long noncoding RNAs (lncRNAs) have emerged as crucial regulators in cancer development and progression. However, limited lncRNAs involved in CSCs have been reported.MethodsThe novel lncROPM (a regulator of phospholipid metabolism) in breast CSCs (BCSCs) was identified by microarray and validated by qRT-PCR in BCSCs from breast cancer cells and tissues. The clinical significance of lncROPM was evaluated in two breast cancer cohorts and TANRIC database (TCGA-BRCA, RNAseq data). Gain- and loss-of-function assays were performed to examine the role of lncROPM on BCSCs both in vitro and in vivo. The regulatory mechanism of lncROPM was investigated by bioinformatics, RNA FISH, RNA pull-down, luciferase reporter assay, and actinomycin D treatment. PLA2G16-mediated phospholipid metabolism was determined by UHPLC-QTOFMS system. Cells' chemosensitivity was assessed by CCK8 assay.ResultsLncROPM is highly expressed in BCSCs. The enhanced lncROPM exists in clinic breast tumors and other solid tumors and positively correlates with malignant grade/stage and poor prognosis in breast cancer patients. Gain- and loss-of-function studies show that lncROPM is required for the maintenance of BCSCs properties both in vitro and in vivo. Mechanistically, lncROPM regulates PLA2G16 expression by directly binding to 3'-UTR of PLA2G16 to increase the mRNA stability. The increased PLA2G16 significantly promotes phospholipid metabolism and the production of free fatty acid, especially arachidonic acid in BCSCs, thereby activating PI3K/AKT, Wnt/β-catenin, and Hippo/YAP signaling, thus eventually involving in the maintenance of BCSCs stemness. Importantly, lncROPM and PLA2G16 notably contribute to BCSCs chemo-resistance. Administration of BCSCs using clinic therapeutic drugs such as doxorubicin, cisplatin, or tamoxifen combined with Giripladib (an inhibitor of cytoplasmic phospholipase A2) can efficiently eliminate BCSCs and tumorigenesis.ConclusionsOur study highlights that lncROPM and its target PLA2G16 play crucial roles in sustaining BCSC properties and may serve as a biomarker for BCSCs or other cancer stem cells. Targeting lncROPM-PLA2G16 signaling axis may be a novel therapeutic strategy for patients with breast cancer.
| S-EPMC8555326 | biostudies-literature
Project description:Glioblastoma (GBM) displays marked cellular and metabolic heterogeneity that varies among cellular microenvironments within a tumor. Metabolic targeting has long been advocated as a therapy against many tumors including GBM, but how lipid metabolism is altered to suit different microenvironmental conditions and whether cancer stem cells (CSCs) have altered lipid metabolism are outstanding questions in the field. We interrogated gene expression in separate microenvironments of GBM organoid models that mimic the transition between nutrient-rich and nutrient-poor pseudopalisading/perinecrotic tumor zones using spatial-capture RNA-sequencing. We revealed a striking difference in lipid processing gene expression and total lipid content between diverse cell populations from the same patient, with lipid enrichment in hypoxic organoid cores and also in perinecrotic and pseudopalisading regions of primary patient tumors. This was accompanied by regionally restricted upregulation of hypoxia-inducible lipid droplet-associated (HILPDA) gene expression in organoid cores and pseudopalisading regions of clinical GBM specimens, but not lower-grade brain tumors. CSCs have low lipid droplet accumulation compared to non-CSCs in organoid models and xenograft tumors, and prospectively sorted lipid-low GBM cells are functionally enriched for stem cell activity. Targeted lipidomic analysis of multiple patient-derived models revealed a significant shift in lipid metabolism between GBM CSCs and non-CSCs, suggesting that lipid levels may not be simply a product of the microenvironment but also may be a reflection of cellular state. CSCs had decreased levels of major classes of neutral lipids compared to non-CSCs, but had significantly increased polyunsaturated fatty acid production due to high fatty acid desaturase (FADS1/2) expression which was essential to maintain CSC viability and self-renewal. Our data demonstrate spatially and hierarchically distinct lipid metabolism phenotypes occur clinically in the majority of patients, can be recapitulated in laboratory models, and may represent therapeutic targets for GBM.
| S-EPMC8166002 | biostudies-literature