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A multidimensional atlas of human glioblastoma-like organoids reveals highly coordinated molecular networks and effective drugs

ABSTRACT: Genome-wide DNA Methylation array on iPSCs and organoids with different genetic mutations.

ORGANISM(S): Homo sapiens

PROVIDER: GSE213554 | GEO | 2024/01/26

REPOSITORIES: GEO

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A multidimensional atlas of human glioblastoma-like organoids reveals highly coordinated molecular networks and effective drugs.

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A multidimensional atlas of human glioblastoma-like organoids reveals highly coordinated molecular networks and effective drugs [RNA-seq]

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A multidimensional atlas of human glioblastoma-like organoids reveals highly coordinated molecular networks and effective drugs

Project description:A multidimensional atlas of human glioblastoma-like organoids reveals highly coordinated molecular networks and effective drugs

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A multidimensional atlas of human glioblastoma-like organoids reveals highly coordinated molecular networks and effective drugs [RNA-seq]

Project description:A multidimensional atlas of human glioblastoma-like organoids reveals highly coordinated molecular networks and effective drugs [RNA-seq]

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Bone marrow derived myeloid cells orchestrate antiangiogenic resistance in glioblastoma through coordinated molecular networks.

Project description:Glioblastoma (GBM) is a hypervascular and malignant form of brain tumors. Anti-angiogenic therapies (AAT) were used as an adjuvant against VEGF-VEGFR pathway to normalize blood vessels in clinical and preclinical studies, which resulted into marked hypoxia and recruited bone marrow derived cells (BMDCs) to the tumor microenvironment (TME). In vivo animal models to track BMDCs and investigate molecular mechanisms in AAT resistance are rare. We exploited recently established chimeric mouse to develop orthotopic U251 tumor, which uses as low as 5 × 10(6) GFP+ BM cells in athymic nude mice and engrafted >70% GFP+ cells within 14 days. Our unpublished data and published studies have indicated the involvement of immunosuppressive myeloid cells in therapeutic resistance in glioma. Similarly, in the present study, vatalanib significantly increased CD68+ myeloid cells, and CD133+, CD34+ and Tie2+ endothelial cell signatures. Therefore, we tested inhibition of CSF1R+ myeloid cells using GW2580 that reduced tumor growth by decreasing myeloid (Gr1+ CD11b+ and F4/80+) and angiogenic (CD202b+ and VEGFR2+) cell signatures in TME. CSF1R blockade significantly decreased inflammatory, proangiogenic and immunosuppressive molecular signatures compared to vehicle, vatalanib or combination. TCK1 or CXCL7, a potent chemoattractant and activator of neutrophils, was observed as most significantly decreased cytokine in CSF1R blockade. ERK MAPK pathway was involved in cytokine network regulation. In conclusion, present study confirmed the contribution of myeloid cells in GBM development and therapeutic resistance using chimeric mouse model. We identified novel molecular networks including CXCL7 chemokine as a promising target for future studies. Nonetheless, survival studies are required to assess the beneficial effect of CSF1R blockade.

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Self-Organized Cerebral Organoids with Human-Specific Features Predict Effective Drugs to Combat Zika Virus Infection.

Project description:The human cerebral cortex possesses distinct structural and functional features that are not found in the lower species traditionally used to model brain development and disease. Accordingly, considerable attention has been placed on the development of methods to direct pluripotent stem cells to form human brain-like structures termed organoids. However, many organoid differentiation protocols are inefficient and display marked variability in their ability to recapitulate the three-dimensional architecture and course of neurogenesis in the developing human brain. Here, we describe optimized organoid culture methods that efficiently and reliably produce cortical and basal ganglia structures similar to those in the human fetal brain in vivo. Neurons within the organoids are functional and exhibit network-like activities. We further demonstrate the utility of this organoid system for modeling the teratogenic effects of Zika virus on the developing brain and identifying more susceptibility receptors and therapeutic compounds that can mitigate its destructive actions.

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Self-organized cerebral organoids with human specific features predict effective drugs to combat Zika virus infection

Project description:This SuperSeries is composed of the SubSeries listed below.

2017-10-11 | GSE104279 | GEO

Glioblastoma Model Using Human Cerebral Organoids.

Project description:We have developed a cancer model of gliomas in human cerebral organoids that allows direct observation of tumor initiation as well as continuous microscopic observations. We used CRISPR/Cas9 technology to target an HRasG12V-IRES-tdTomato construct by homologous recombination into the TP53 locus. Results show that transformed cells rapidly become invasive and destroy surrounding organoid structures, overwhelming the entire organoid. Tumor cells in the organoids can be orthotopically xenografted into immunodeficient NOD/SCID IL2RG-/- animals, exhibiting an invasive phenotype. Organoid-generated putative tumor cells show gene expression profiles consistent with mesenchymal subtype human glioblastoma. We further demonstrate that human-organoid-derived tumor cell lines or primary human-patient-derived glioblastoma cell lines can be transplanted into human cerebral organoids to establish invasive tumor-like structures. Our results show potential for the use of organoids as a platform to test human cancer phenotypes that recapitulate key aspects of malignancy.

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The efficacy of a coordinated pharmacological blockade in glioblastoma stem cells with nine repurposed drugs using the CUSP9 strategy.

Project description:PURPOSE:Constructed from a theoretical framework, the coordinated undermining of survival paths in glioblastoma (GBM) is a combination of nine drugs approved for non-oncological indications (CUSP9; aprepitant, auranofin, captopril, celecoxib, disulfiram, itraconazole, minocycline, quetiapine, and sertraline) combined with temozolomide (TMZ). The availability of these drugs outside of specialized treatment centers has led patients to embark on combination treatments without systematic follow-up. However, no experimental data on efficacy using the CUSP9 strategy in GBM have been reported. METHODS:Using patient-derived glioblastoma stem cell (GSC) cultures from 15 GBM patients, we described stem cell properties of individual cultures, determined the dose-response relationships of the drugs in the CUSP9, and assessed the efficacy the CUSP9 combination with TMZ in concentrations clinically achievable. The efficacy was evaluated by cell viability, cytotoxicity, and sphere-forming assays in both primary and recurrent GSC cultures. RESULTS:We found that CUSP9 with TMZ induced a combination effect compared to the drugs individually (p?<?0.0001). Evaluated by cell viability and cytotoxicity, 50% of the GSC cultures displayed a high sensitivity to the drug combination. In clinical plasma concentrations, the effect of the CUSP9 with TMZ was superior to TMZ monotherapy (p?<?0.001). The Wnt-signaling pathway has been shown important in GSC, and CUSP9 significantly reduces Wnt-activity. CONCLUSIONS:Adding experimental data to the theoretical rationale of CUSP9, our results demonstrate that the CUSP9 treatment strategy can induce a combination effect in both treatment-naïve and pretreated GSC cultures; however, predicting response in individual cultures will require further profiling of GSCs.

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Biotemplated CdS Nano-Aggregate Networks for Highly Effective Visible-Light Photocatalytic Hydrogen Production.

Project description:In the last few decades, many new synthesis techniques have been developed in order to obtain an effective visible-light responsive photocatalyst for hydrogen production by water splitting. Among these new approaches, the biotemplated synthesis method has aroused much attention because of its unique advantages in preparing materials with special morphology and structure. In this work, Hydrilla verticillata (L. f.) Royle was used as a biotemplate to synthesize a CdS photocatalyst. The as-synthesized sample had the microstructure of nano-scaled aggregate networks and its activity for photocatalytic hydrogen production was six times higher than that of CdS synthesized without a template in an Na2S-Na2SO3 sacrificial system. The use of Pt and PdS as cocatalysts further improved the hydrogen production rate to 14.86 mmol/g·h under visible-light (λ ≥ 420 nm) irradiation, so the hydrogen production can be directly observed by the naked eye. The results of characterization showed that the as-synthesized CdS photocatalyst has a high specific surface area and narrow band gap, which is favorable for light absorption and photocatalytic reaction. This work provides a new way to search for efficient visible-light catalysts and confirms the uniqueness of a biotemplated synthesis method in obtaining specially structured materials.

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