Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA117521 | ENA |
REPOSITORIES: ENA
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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.
2022-06-02 | PXD021429 | Pride
Project description:Despite the progress in medicine, no significant advancement in the standard of care for glioblastoma (GBM) patients have been reached. GBM heterogeneity, poor blood–brain barrier penetration and resistance to therapy highlight the need for new targets and clinical treatments. A step toward clinical translation includes the eradication of GBM Tumor-Initiating Cells (TICs), responsible for GBM heterogeneity and relapse. By using patient-derived TICs and xenograft orthotopic models, we demonstrate that Lysine-specific histone demethylase 1A (LSD1) is a druggable target in GBM. Here, we analyze the effect of LSD1i treatment on histone H3K4 in primary human cells and mouse brains.
2022-04-14 | PXD025781 | Pride
Project description:The aim of this study is to determine if, using antioxidant drugs, it is possible to interfere with the proliferative capabilities of the human glioblastoma (GBM) tumor-initiating cells (TICs). To establish which cellular processes are activated in GBM TICs by the antioxidants NAC, Tiron and Trolox, we generated and analyzed the gene expression profiles after treatment with these compounds and with H2O and EtOH (vehicles).
2014-03-04 | E-GEOD-44099 | biostudies-arrayexpress
Project description:The aim of this study is to determine if, using antioxidant drugs, it is possible to interfere with the proliferative capabilities of the human glioblastoma (GBM) tumor-initiating cells (TICs).
2014-03-04 | GSE44099 | GEO
Project description:Most patients affected by Glioblastoma multiforme (GBM) experience a recurrence of the disease because of the spreading of tumor-initiating cells (TICs) beyond surgical boundary. Unveiling and targeting molecular mechanisms causing this process is a logic goal to impair GBM killing ability. In an orthotopic xenograph model, we have noticed that GBM TICs isolated from several patients may fall into two classes of invasive behavior: nodular or diffuse. In order to identify genes responsible for the diffusive type of invasion, we have compared by genome expression analysis, cultured GBM TICs belonging to the two classes. This analysis allowed us to identify a small group of regulated genes in the diffusive type of GBM TICs. The gene ontology process of cell adhesion and the localization of the gene product functions to the plasmamembrane resulted significantly associated to this gene set. Real time RT-PCR and immunofluorescence analyses performed for a selected subgroup of regulated genes/gene products confirmed the results obtained by the expression analysis. Some of the genes that we found upregulated in our screening were already proven to be involved in Glioma cell invasion supporting our study. However, we have also identified genes that were not previously implicated in this process. To assess whether these are required to sustain TICs GBM invasion, we silenced a subset of them and evaluated in Boyden chamber the invasive ability of the cells. Our study provides novel target genes to be evaluated for the inhibition of GBM diffusion within the SNC. As we observed that GBM TICs may fall into two classes of M-bM-^@M-^\in vivoM-bM-^@M-^] invasive behavior in mouse orthotopic transplantation: expansive or highly diffusive, resulting in the hostM-bM-^@M-^Ys white and gray matters substitution, we decided to identify genes associated with the latter phenotype by microarray analysis. Three replicates of each class were analyzed.
2012-09-11 | E-GEOD-16805 | biostudies-arrayexpress
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:Most patients affected by Glioblastoma multiforme (GBM) experience a recurrence of the disease because of the spreading of tumor-initiating cells (TICs) beyond surgical boundary. Unveiling and targeting molecular mechanisms causing this process is a logic goal to impair GBM killing ability. In an orthotopic xenograph model, we have noticed that GBM TICs isolated from several patients may fall into two classes of invasive behavior: nodular or diffuse. In order to identify genes responsible for the diffusive type of invasion, we have compared by genome expression analysis, cultured GBM TICs belonging to the two classes. This analysis allowed us to identify a small group of regulated genes in the diffusive type of GBM TICs. The gene ontology process of cell adhesion and the localization of the gene product functions to the plasmamembrane resulted significantly associated to this gene set. Real time RT-PCR and immunofluorescence analyses performed for a selected subgroup of regulated genes/gene products confirmed the results obtained by the expression analysis. Some of the genes that we found upregulated in our screening were already proven to be involved in Glioma cell invasion supporting our study. However, we have also identified genes that were not previously implicated in this process. To assess whether these are required to sustain TICs GBM invasion, we silenced a subset of them and evaluated in Boyden chamber the invasive ability of the cells. Our study provides novel target genes to be evaluated for the inhibition of GBM diffusion within the SNC.
2012-09-11 | GSE16805 | GEO
Project description:Glioblastomas (GBM) harbor subpopulations of therapy-resistant tumor initiating cells (TICs) that are self-renewing and multipotent. To understand the regulation of the TIC state, we performed an image-based screen for genes regulating GBM TIC maintenance and identified ZFHX4, a 397-kDa transcription factor. ZFHX4 is required to maintain TIC-associated phenotypes in vitro, suggesting that ZFHX4 regulates TIC differentiation, and its suppression increases glioma-free survival in intracranial xenografts. ZFHX4 interacts with CHD4, a core member of the NuRD (nucleosome remodeling and deacetylase) complex. ZFHX4 and CHD4 bind to overlapping sets of genomic loci and control similar gene expression programs. Using expression data derived from GBM patients, we demonstrate ZFHX4 is a master regulator of CHD4-mediated gene expression. These observations define ZFHX4 as a regulatory factor that links the chromatin remodeling NuRD complex and the GBM TIC state. Examination of binding of ZFHX4 and CHD4 across the human genome, using the 0308 tumor initiating cell line. Two replicates for each protein, compared to whole cell extract inputs.
2014-01-16 | E-GEOD-52419 | biostudies-arrayexpress