Similar Datasets
Project description:The goals of WGS (Whole Genome Sequencing) analysis in TJ46 cells derived from a GBM primary tissue to obtain information on the genetic alterations that characterize this model.
2022-09-20 | GSE202644 | GEO
Project description:Tumors often undergo stress and need to reprogram their metabolism to survive and grow under nutrient challenging conditions. The stroma could play a critical role in this process by providing nutrients or signals to support the epithelial compartment of the tumor. Autophagy has been shown to play key roles both in the stroma and in the epithelium. However, how autophagy adaptors, such as p62, participate in the mechanisms whereby the stroma supports tumor progression is not yet fully understood. Here we show that p62 deficiency in stromal fibroblasts promotes resistance to glutamine deprivation through a metabolic reprogramming orchestrated by the direct control of ATF4 stability by p62-mediated polyubiquitination. This, in turn, activates the flux of glucose carbons through a pyruvate carboxylase-asparagine synthase cascade that results in asparagine-mediated stromal cell growth and tumor epithelial proliferation, independent of autophagy. This supports a new model in which p62 directly targets nuclear transcription factors to control metabolic reprograming in the microenvironment to repress tumorigenesis, and emerges as global tumor suppressor.
2018-02-14 | GSE94343 | GEO
Project description:Tumors often undergo stress and need to reprogram their metabolism to survive and grow under nutrient challenging conditions. The stroma could play a critical role in this process by providing nutrients or signals to support the epithelial compartment of the tumor. Autophagy has been shown to play key roles both in the stroma and in the epithelium. However, how autophagy adaptors, such as p62, participate in the mechanisms whereby the stroma supports tumor progression is not yet fully understood. Here we show that p62 deficiency in stromal fibroblasts promotes resistance to glutamine deprivation through a metabolic reprogramming orchestrated by the direct control of ATF4 stability by p62-mediated polyubiquitination. This, in turn, activates the flux of glucose carbons through a pyruvate carboxylase-asparagine synthase cascade that results in asparagine-mediated stromal cell growth and tumor epithelial proliferation, independent of autophagy. This supports a new model in which p62 directly targets nuclear transcription factors to control metabolic reprograming in the microenvironment to repress tumorigenesis, and emerges as global tumor suppressor.
2018-02-14 | GSE94367 | GEO
Project description:Tumor-initiating cells (TICs) play a critical role in glioblastoma (GBM) maintenance being responsible for its heterogeneity and resistance to standard therapy. A step toward clinical translation includes GBM TIC targeting. Among the molecules tested for GBM treatment, are those targeting epigenetic modifiers. By using patient-derived TICs and xenograft orthotopic models, we identified Lysine-specific histone demethylase 1A (LSD1) as a potentially druggable target in GBM. LSD1-directed therapy by means of the selective, orally bioavailable and brain penetrant inhibitor DDP_38003 effectively impairs growth, stem-like features and tumorigenic potential of GBM TICs. Our findings point to LSD1 as a positive regulator of Activating Transcription Factor 4 (ATF4)-dependent response in all stress conditions arising during tumor growth and therapy. Thus, through the downregulation of either ATF4 and its adaptive genes, LSD1 targeting is likely a promising strategy to hit GBM TICs by counteracting the ATF4-mediated adaptation to stress.
2022-01-10 | GSE181372 | GEO
Project description:Tumor-initiating cells (TICs) play a critical role in glioblastoma (GBM) maintenance being responsible for its heterogeneity and resistance to standard therapy. A step toward clinical translation includes GBM TIC targeting. Among the molecules tested for GBM treatment, are those targeting epigenetic modifiers. By using patient-derived TICs and xenograft orthotopic models, we identified Lysine-specific histone demethylase 1A (LSD1) as a potentially druggable target in GBM. LSD1-directed therapy by means of the selective, orally bioavailable and brain penetrant inhibitor DDP_38003 effectively impairs growth, stem-like features and tumorigenic potential of GBM TICs. Our findings point to LSD1 as a positive regulator of Activating Transcription Factor 4 (ATF4)-dependent response in all stress conditions arising during tumor growth and therapy. Thus, through the downregulation of either ATF4 and its adaptive genes, LSD1 targeting is likely a promising strategy to hit GBM TICs by counteracting the ATF4-mediated adaptation to stress.
2022-01-10 | GSE181366 | GEO
Project description:Tumor-initiating cells (TICs) play a critical role in glioblastoma (GBM) maintenance being responsible for its heterogeneity and resistance to standard therapy. A step toward clinical translation includes GBM TIC targeting. Among the molecules tested for GBM treatment, are those targeting epigenetic modifiers. By using patient-derived TICs and xenograft orthotopic models, we identified Lysine-specific histone demethylase 1A (LSD1) as a potentially druggable target in GBM. LSD1-directed therapy by means of the selective, orally bioavailable and brain penetrant inhibitor DDP_38003 effectively impairs growth, stem-like features and tumorigenic potential of GBM TICs. Our findings point to LSD1 as a positive regulator of Activating Transcription Factor 4 (ATF4)-dependent response in all stress conditions arising during tumor growth and therapy. Thus, through the downregulation of either ATF4 and its adaptive genes, LSD1 targeting is likely a promising strategy to hit GBM TICs by counteracting the ATF4-mediated adaptation to stress.
2022-01-10 | GSE181378 | GEO
Project description:The integrated stress response (ISR) controls cellular adaptations to nutrient deprivation, redox imbalances and ER stress. ISR genes are upregulated in stressed cells, primarily by the bZIP transcription factor ATF4 through its recruitment to cis-regulatory C/EBP:ATF response elements (CAREs) together with a dimeric partner of uncertain identity. Here we show that C/EBPγ:ATF4 heterodimers, but not C/EBPβ:ATF4 dimers, are the predominant CARE binding species in stressed cells. C/EBPγ and ATF4 associate with genomic CAREs in a mutually-dependent manner and co-regulate many ISR genes. By contrast, the C/EBP family members C/EBPβ and CHOP were largely dispensable for induction of stress genes. Cebpgâ/â MEFs proliferate poorly and exhibit oxidative stress due to reduced glutathione levels and impaired expression of several glutathione biosynthesis pathway genes. Cebpgâ/â mice (C57BL/6 background) display reduced body size and microphthalmia, similar to ATF4-null animals. In addition, C/EBPγ-deficient newborns die from atelectasis and respiratory failure which can be mitigated by in utero exposure to the anti-oxidant, N-acetyl-cysteine. Cebpgâ/â mice on a mixed strain background show improved viability but, upon aging, develop significantly fewer malignant solid tumors compared to WT animals. Our findings identify C/EBPγ as a novel anti-oxidant regulator and an obligatory ATF4 partner that controls redox homeostasis in normal and cancerous cells. Evaluation of genomic binding of 2 bZIP transcription factors under amino acid deprivation conditions in mouse embryonic fibroblasts
2015-11-19 | E-GEOD-75165 | biostudies-arrayexpress
Project description:Gene expression profiling was performed to identify Siah2-dependent changes in cells subjected to ER stress, hypoxia, and combined glucose/oxygen deprivation. To establish the magnitude of the Siah2 effect on the ER stress response, we have compared gene expression profiles of WT and Siah1a-/-::Siah2-/- mouse embryo fibroblasts (MEFs) that were subjected to glycosylation inhibitor tunicamycin (TM), thapsigargin (TG), glucose deprivation, or glucose/oxygen deprivation. Overall, this analysis confirmed changes associated with ER stress that had not previously been associated with Siah2 signaling, substantiating Siah2 as a key coordinator of ER stress through the ATF4 and sXbp1 pathways. WT and Siah1a/Siah2 KO MEF cells were treated with TM or TG for 6 h, or subjected for 12 h to oxygen deprivation, glucose deprivation or a combination of oxygen and glucose deprivation, in duplicate.
2014-04-01 | E-GEOD-39244 | biostudies-arrayexpress
Project description:Macrophages are critical components of the immunosuppressive microenvironment that restrict anti-cancer immunity in glioblastoma (GBM). However, how GBM shapes the regulatory function of macrophages remains elusive. Here, we report that monocyte-derived macrophages (MDM), but not yolk-sac derived microglia (MG), exhibited potent immunosuppressive activity, which was mediated by a population of glycolytic GLUT1+MDM, in an IL10-dependent manner. GBM-derived factors reprogrammed MDM towards glycolytic cells with enhanced avidity for glucose, which was mostly used to generate lactate. In turn, intracellular lactate caused lactylation of histone lysine residues that promoted MDM immunosuppressive activity via regulation of Il10 expression. GBM-primed activation of PERK supported glucose metabolism and regulated GLUT1 expression through ATF4 in MDM. PERK-deletion in MDM abrogated histone lactylation and suppressive activity, thereby promoting polyfunctional T cell-infiltration of tumors. In combination with immunotherapy, PERK-deletion blocked GBM progression. Our study demonstrates that glucose-driven histone lactylation controls MDM immunosuppressive function; all in a PERK-dependent manner.
2024-05-06 | GSE260701 | GEO
Project description:For additional details see Ebert et al, Identification and Small Molecule Inhibition of an ATF4-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy. Quadriceps femoris muscles were harvested from 22-month-old muscle-specfic ATF4 knockout (ATF4 mKO) mice and littermate controls. mRNA levels in ATF4 mKO muscles were normalized to levels in littermate control muscles.
2015-09-03 | E-GEOD-72658 | biostudies-arrayexpress