Genome-wide gene expression profile of human DIPG cell lines (ONC201 treatment)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE239939 | GEO | 2023/12/31
REPOSITORIES: GEO
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Project description:To study the chromatin accessibility across the genome of DIPG-VII, DIPG-IV, and DIPG-XIII cell lines, we performed ATACseq (Assay for Transposase-Accessible Chromatin with high-throughput sequencing).
2023-12-31 | GSE239938 | GEO
Project description:Genome-wide gene expression profile of human DIPG cell lines (ONC201 treatment)
| PRJNA1001515 | ENA
Project description:Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of all childhood cancers. Palliative radiotherapy is the only proven life-prolonging treatment, with patient survival 9-11 months. ONC201 shows preclinical and emerging clinical efficacy in DIPG. Currently, little is known about the mechanisms of sensitivity/resistance of DIPGs to ONC201, or whether recurring genomic features influence response. Using a systems-biological approach, we show ONC201 elicits potent agonism of the mitochondrial protease, CLPP, driving proteolysis of electron transport chain (ETC) and tricarboxylic acid (TCA) cycle proteins. DIPGs harboring TP53-mutations show reduced sensitivity to ONC201. Molecular mechanisms identify metabolic adaptation and resistance to ONC201 regulated by redox-activated PI3K/Akt signaling, counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib, in both wt-TP53 and TP53-mutant DIPGs. The discoveries described within, coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib inform the DIPG/DMG phase II combination clinical trial NCT05009992.
2023-05-25 | PXD036245 | Pride
Project description:The small molecule ONC201 is toxic in vitro to multiple cell lines and primary tumor samples of mantle cell lymphoma (MCL) and acute myeloid leukemia, even ones with unfavorable genetic features (notably including TP53 inactivation) or acquired resistance to other agents. Because the mechanism of action in these malignant hematologic cells appeared to differ from that in solid tumors, we performed gene expression profiling (GEP) studies on MCL lines treated with ONC201 and other agents with known mechanisms of action. Treatment of JeKo-1 cells with 5 uM ONC201 showed consistent and progressive increases or decreases over time in two sets of genes: upregulated genes, which implicated an ER stress response and mTOR pathway inhibition, and downregulated genes, which implicated reduced proliferation. These implicated effects of ONC201 were validated by confirmatory experiments. Similar GEP changes were observed in ONC201-naive Z138 cells after 24 hr of ONC201 treatment, but were not seen in Z138 cells made ONC201-resistant by chronic exposure. Finally, the GEP effects of ONC201 in JeKo-1 cells were mimicked by the ER stress inducer tunicamycin, but not by the direct MTOR inhibition rapamycin, further confirming an ER stress response and suggesting that inhibition of the mTOR pathway was by an indirect mechanism. For each experiment, cells from a single stock culture of each cell line used were aliquoted into individual culture plate wells, establishing individual replicates, and drugs were added to start the experiment. Treated replicates were harvested after the times of treatment indicated, by pelleting cells, lysing pellets in TriZOL, and freezing TriZOL until RNA isolation. Untreated replicates, serving as controls, were either harvested at the beginning of the experiment or at later times, as specified below.
2016-02-20 | E-GEOD-68091 | biostudies-arrayexpress
Project description:The small molecule ONC201 is toxic in vitro to multiple cell lines and primary tumor samples of mantle cell lymphoma (MCL) and acute myeloid leukemia, even ones with unfavorable genetic features (notably including TP53 inactivation) or acquired resistance to other agents. Because the mechanism of action in these malignant hematologic cells appeared to differ from that in solid tumors, we performed gene expression profiling (GEP) studies on MCL lines treated with ONC201 and other agents with known mechanisms of action. Treatment of JeKo-1 cells with 5 uM ONC201 showed consistent and progressive increases or decreases over time in two sets of genes: upregulated genes, which implicated an ER stress response and mTOR pathway inhibition, and downregulated genes, which implicated reduced proliferation. These implicated effects of ONC201 were validated by confirmatory experiments. Similar GEP changes were observed in ONC201-naive Z138 cells after 24 hr of ONC201 treatment, but were not seen in Z138 cells made ONC201-resistant by chronic exposure. Finally, the GEP effects of ONC201 in JeKo-1 cells were mimicked by the ER stress inducer tunicamycin, but not by the direct MTOR inhibition rapamycin, further confirming an ER stress response and suggesting that inhibition of the mTOR pathway was by an indirect mechanism.
2016-02-20 | GSE68091 | GEO
Project description:Two experiments were performed with ONC201/TIC10 in human colon cancer cell lines. The first experiment is TIC10-induced transcriptional changes at 48hrs in HCT116 p53-null cells (10uM). The second experiment is RKO cells, with and without acquired resistance to ONC201, treated with with ONC201 (10uM) for 48 hrs. For the first experiment, six samples of HCT116 p53-null cells with TIC10 (10uM) or DMSO treatment. Three replicates each. For the second experiment, six samples of wild-type RKO cells with ONC201 (10uM) or DMSO treatment and the same treatments for RKO cells with acquired resistance to ONC201.
2016-06-01 | E-GEOD-72865 | biostudies-arrayexpress
Project description:Two experiments were performed with ONC201/TIC10 in human colon cancer cell lines. The first experiment is TIC10-induced transcriptional changes at 48hrs in HCT116 p53-null cells (10uM). The second experiment is RKO cells, with and without acquired resistance to ONC201, treated with with ONC201 (10uM) for 48 hrs.
2016-06-01 | GSE72865 | GEO
Project description:Diffuse intrinsic pontine glioma (DIPG) is a rare pediatric brain tumor with a median survival of 10-15 months. Histone H3 is mutated in 80% of DIPGs, dictating tumor location, onset, and outcome. Therapeutic resistance remains a major obstacle to preventing tumor recurrence and is in part driven by cancer stem cells (CSCs), which exhibit self-renewal properties and tumorigenic potential. In previous studies, we have identified these proliferative and tumorigenic features in aldehyde dehydrogenase positive (ALDH+) CSCs in H3K27M mutant DIPG. We hypothesize that ALDH-mediated cancer stemness and resistance may in part be driven by H3K27M. ALDH1A3 expression was reduced in CRISPR-edited DIPG cells (SU-DIPG-XIII) where the H3K27M mutation had been removed (H3K27M-KO). Furthermore, these gained differentiation characteristics and lost their neurosphere-forming potential. The parental (H3K27M) and H3K27M-KO cells were also subjected to ionizing radiation to identify genes responsible for radioresistance in histone-mutated DIPG radioresistance. Nascent transcriptomes were obtained from these cells using bromouridine labeling and capture followed by sequencing (Bru-seq).
2023-08-30 | GSE211833 | GEO
Project description:DIPG is a devastating paediatric and young adult brainstem tumour with no cure and a median overall survival of 9 months. Cellular immunotherapy approaches require specific targeting of unique and tumour specific cell surface antigens, however, there is a paucity of known targets for DIPG. Here we used a proteomics platform approach to interrogate an array of patient derived DIPG cell lines to facilitate a multi-omics based approach to identify cell surface protein candidates enriched or unique to DIPG.
2023-09-25 | PXD038271 | Pride
Project description:Cultured pediatric high-grade glioma cell lines (SU-DIPG-IV, HSJD-DIPG-007, HSJD-GBM-001,BT 245 (RRID:CVCL_IP13)) were treated with selinexor (Karyopharm Therapeutics) at 5xIC50 for 16 hours or vehicle (0.1% DMSO) followed by bulk RNA-Seq
2020-01-06 | GSE137702 | GEO