3D Tumor Tissue Analogs: Tumor Microenvironment and Therapeutic Implications in DIPG
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE222891 | GEO | 2025/09/22
REPOSITORIES: GEO
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Project description:3D Tumor Tissue Analogs: Tumor Microenvironment and Therapeutic Implications in DIPG
| PRJNA923708 | ENA
Project description:Diffuse intrinsic pontine glioma (DIPG) is a universally fatal malignancy of the childhood central nervous system, with a median overall survival of 9-11 months. We have previously shown that primary DIPG tissue contains numerous tumor-associated macrophages, and substantial work has demonstrated a significant pathological role for adult glioma-associated macrophages. However, work over the past decade has highlighted many molecular and genomic differences between pediatric and adult glioblastomas (GBM). Thus, we directly compared inflammatory characteristics of DIPG and adult GBM. We found that the leukocyte (CD45+) compartment in primary DIPG tissue samples is predominantly composed of CD11b+ macrophages, with very few CD3+ T-lymphocytes. In contrast, T-lymphocytes are more abundant in adult GBM tissue samples. RNA sequencing of macrophages isolated from primary tumor samples revealed that DIPG- and adult GBM-associated macrophages both express gene programs related to ECM remodeling and angiogenesis, but DIPG-associated macrophages express substantially fewer inflammatory factors than their adult GBM counterparts. Examining the secretome of glioma cells, we found that patient-derived DIPG cell cultures secrete markedly fewer cytokines and chemokines than patient-derived adult GBM cultures. Concordantly, bulk and single-cell RNA sequencing data indicates low to absent expression of chemokines and cytokines in DIPG. Together, these observations suggest that the inflammatory milieu of the DIPG tumor microenvironment is fundamentally different than adult GBM. The low intrinsic inflammatory signature of DIPG cells may contribute to the lack of lymphocytes and non-inflammatory phenotype of DIPG-associated microglia/macrophages. Understanding the glioma subtype-specific inflammatory milieu may inform the design and application of immunotherapy-based treatments.
2018-08-23 | GSE115397 | GEO
Project description:We studied the effect of BMI1 inhibition in diffuse intrinsic pontine glioma cells (DIPG). We reported the application of chromatin immunoprecipitation sequencing for high-thoughput profiling of BMI1 and H2AK119ub in diffuse intrinsic pontine glioma cells (DIPG) in response to BMI1 inhibition. We also performed bulk RNA sequencing of DIPG cells in response to pharmacological inhibition or knockdown of BMI1.
2020-10-22 | GSE140768 | GEO
Project description:Histone H3 lysine 27 to methionine mutations (H3K27M) resulting in aberrant chromatin regulation are frequently observed in Diffuse Intrinsic Pontine Glioma (DIPG), a pediatric brain tumor with no cure. We conducted a CRISPR screen to determine if various chromatin regulators might be targeted to treat DIPG. Excitingly, this genetic screen reveals that co-targeting lysine specific demethylase 1 (LSD1) and histone deacetylases (HDACs) results in an enhanced growth suppressive effect in patient DIPG cells. Consistent with the genetic screen, a bifunctional inhibitor of HDACs and LSD1, Corin, inhibits DIPG growth in vitro and in xenografts. Mechanistically, Corin rescues H3K27me3 levels typically suppressed by the dominant effects of H3K27M mutations in DIPG and simultaneously increases HDAC-targeted H3K27ac and LSD1-targeted H3K4me1 at enhancers. Further studies reveal that Corin de-regulates DIPG transcription resulting in cell death, cell cycle arrest, and the induction of neuronal differentiation. These data suggest that co-targeting LSD1 and HDACs may represent a novel strategy for treating DIPG.
2019-09-26 | GSE110571 | GEO
Project description:Histone H3 lysine 27 to methionine mutations (H3K27M) resulting in aberrant chromatin regulation are frequently observed in Diffuse Intrinsic Pontine Glioma (DIPG), a pediatric brain tumor with no cure. We conducted a CRISPR screen to determine if various chromatin regulators might be targeted to treat DIPG. Excitingly, this genetic screen reveals that co-targeting lysine specific demethylase 1 (LSD1) and histone deacetylases (HDACs) results in an enhanced growth suppressive effect in patient DIPG cells. Consistent with the genetic screen, a bifunctional inhibitor of HDACs and LSD1, Corin, inhibits DIPG growth in vitro and in xenografts. Mechanistically, Corin rescues H3K27me3 levels typically suppressed by the dominant effects of H3K27M mutations in DIPG and simultaneously increases HDAC-targeted H3K27ac and LSD1-targeted H3K4me1 at enhancers. Further studies reveal that Corin de-regulates DIPG transcription resulting in cell death, cell cycle arrest, and the induction of neuronal differentiation. These data suggest that co-targeting LSD1 and HDACs may represent a novel strategy for treating DIPG.
2019-09-25 | GSE110570 | GEO
Project description:H3K27M diffuse intrinsic pontine gliomas (DIPG) exhibit cellular heterogeneity comprising less-differentiated, stem-like glioma cells that resemble oligodendrocyte precursors (OPC) and more differentiated astrocyte (AC)-like cells. H3K27M DIPG stem-like cells exhibit tumor-seeding capabilities in vivo, a feature lost or greatly diminished in the more differentiated AC-like cells. In this study, we established isogenic in vitro models of DIPG that closely recapitulated the OPC-like and AC-like phenotypes of DIPG cells. Using these tools, we performed transcriptomics, metabolomics, and bioenergetic profiling to identify metabolic programs operative in the different cellular states. From this, we defined new strategies to selectively target metabolic vulnerabilities within the specific tumor populations. Namely, we showed that the AC-like cells exhibited a more mesenchymal phenotype and were thus sensitized to ferroptotic cell death. In contrast, OPC-like cells upregulated cholesterol metabolism and mitochondrial oxidative phosphorylation (OXPHOS) and were accordingly more sensitive to statins and OXPHOS inhibitors. Additionally, statins and OXPHOS inhibitors showed efficacy and extended survival in preclinical orthotopic models established with stem-like H3K27M DIPG cells. Together, this study demonstrates that cellular subtypes within DIPGs harbor distinct metabolic vulnerabilities that can be uniquely and selectively targeted for therapeutic gain.
2022-03-21 | GSE197145 | GEO
Project description:Non-inflammatory tumor microenvironment of Diffuse Intrinsic Pontine Glioma (DIPG)
| PRJNA474825 | ENA
Project description:<p>Diffuse Intrinsic Pontine Glioma (DIPG) is a universally fatal childhood cancer. Here, we performed a chemical screen in patient-derived DIPG cell cultures along with RNAseq expression analysis and integrated computational modeling to identify potentially effective therapeutic strategies. Panobinostat, among the more promising agents identified, demonstrated efficacy in pontine orthotopic xenograft models of both H3K27M and histone WT DIPG. These data suggest the potential utility of specific drug combinations and provides evidence of in vivo treatment efficacy of the multi-histone deacetylase inhibitor panobinostat. We are depositing to dbGaP deep sequencing whole exome data for 22 patient tumor samples and 13 matched normals, along with RNAseq data for 12 patient tumor samples and 6 normal pediatric brain tissue samples. In addition, we are depositing 22 RNAseq samples from DIPG cell lines before and after panobinostat treatment.</p>
| phs000900 | dbGaP
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:Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. A high throughput drug screen of 3600 pharmaceutical compounds found that anti-malarials, including quinacrine had potent activity against DIPG neurospheres. CBL0137 is a novel anti-cancer compound developed from quinacrine, which targets Facilitates Chromatin Transcription (FACT), a chromatin remodelling complex involved in transcription, replication, and DNA repair. We have found that CBL0137 displays profound cytotoxic activity against a panel of patient derived DIPG cultures, inhibiting cell proliferation and clonogenic potential, restoring tumor suppressor TP53 and Rb activity and inducing cell death through induction of apoptosis. Moreover, in an orthotopic model of DIPG, treatment with CBL0137 significantly extended animal survival. Histone mutations leading to the loss of histone trimethylation result in epigenetic dysregulation driving DIPG tumorigenesis. Treatment with CBL0137 targets this epigenetic defect, restoring both histone H3.3 acetylation and trimethylation and leading to tumor cell death. Combined epigenetic treatment with the histone deacetylase (HDAC) inhibitor panobinostat led to inhibition of the Rb/E2F1 pathway, and increased the enzymatic activity of enhancer of zeste homolog 2 (EZH2), leading to the restoration of H3K27 trimethylation. This combination therapy had synergistic activity against DIPG neurospheres with induction of apoptosis. Consistent with the in vitro results, the combination of CBL0137 and panobinostat significantly prolonged the survival of mice bearing DIPG orthografts suggesting a potential treatment strategy for DIPG.
2021-03-07 | GSE153883 | GEO