Single-cell/single-nucleus RNA-seq of diffuse hemispheric gliomas, H3G34-mutant.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE162989 | GEO | 2024/07/30
REPOSITORIES: GEO
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Project description:Diffuse hemispheric gliomas, H3G34R/V-mutant (DHG-H3G34), are uniformly lethal malignancies lacking targeted therapies. These gliomas uniquely originate from interneuronal precursor cells, and leveraging this interneuronal lineage origin for mechanistic and therapeutic insights is a pressing need. Here, we elucidate the cell state composition of DHG-H3G34, resolving a cellular hierarchy along continuous interneuron lineage development. In the developing human brain, interneuron lineage precursors form characteristic histological patterns organized in streams of progenitor cells surrounding nests of migratory interneurons, and we find these same spatial patterns to be mirrored in primary DHG-H3G34 tumors. We integrated these findings with genome-wide CRISPR-Cas9 screens, which revealed the majority of dependencies to be genes upregulated in interneuron lineage progenitors, highlighting these as a driver of DHG-H3G34. We validated the essentiality of these lineage-associated targets in patient-derived in vitro and in vivo models. Among these, CDK6 emerged as a targetable dependency, and we demonstrated enhanced sensitivity of DHG-H3G34 tumor cells to CDK4/6 inhibitors and a CDK6-specific degrader. Inhibition of CDK6 shifted cells towards more mature interneuron-like cell states, reduced tumor growth, and prolonged survival of patient-derived xenografts. Concordantly, a patient with progressive DHG-H3G34 under second line therapy was treated with a CDK4/6 inhibitor, and exhibited stable disease for 17 months. Collectively, we identify interneuronal progenitor-like states, organized in characteristic developmental spatial niches, as a distinct vulnerability consistently upregulated in DHG-H3G34 tumors, and provide initial evidence for CDK6 as a clinically actionable target particularly relevant for its interneuronal developmental biology.
2024-08-01 | GSE272262 | GEO
Project description:Diffuse hemispheric gliomas, H3G34R/V-mutant (DHG-H3G34), are uniformly lethal malignancies lacking targeted therapies. These gliomas uniquely originate from interneuronal precursor cells, and leveraging this interneuronal lineage origin for mechanistic and therapeutic insights is a pressing need. Here, we elucidate the cell state composition of DHG-H3G34, resolving a cellular hierarchy along continuous interneuron lineage development. In the developing human brain, interneuron lineage precursors form characteristic histological patterns organized in streams of progenitor cells surrounding nests of migratory interneurons, and we find these same spatial patterns to be mirrored in primary DHG-H3G34 tumors. We integrated these findings with genome-wide CRISPR-Cas9 screens, which revealed the majority of dependencies to be genes upregulated in interneuron lineage progenitors, highlighting these as a driver of DHG-H3G34. We validated the essentiality of these lineage-associated targets in patient-derived in vitro and in vivo models. Among these, CDK6 emerged as a targetable dependency, and we demonstrated enhanced sensitivity of DHG-H3G34 tumor cells to CDK4/6 inhibitors and a CDK6-specific degrader. Inhibition of CDK6 shifted cells towards more mature interneuron-like cell states, reduced tumor growth, and prolonged survival of patient-derived xenografts. Concordantly, a patient with progressive DHG-H3G34 under second line therapy was treated with a CDK4/6 inhibitor, and exhibited stable disease for 17 months. Collectively, we identify interneuronal progenitor-like states, organized in characteristic developmental spatial niches, as a distinct vulnerability consistently upregulated in DHG-H3G34 tumors, and provide initial evidence for CDK6 as a clinically actionable target particularly relevant for its interneuronal developmental biology.
2024-08-01 | GSE272261 | GEO
Project description:This phase I trial studies the side effects and best dose of pembrolizumab and to see how well it works in treating younger patients with high-grade gliomas (brain tumors that are generally expected to be fast growing and aggressive), diffuse intrinsic pontine gliomas (brain stem tumors), brain tumors with a high number of genetic mutations, ependymoma or medulloblastoma that have come back (recurrent), progressed, or have not responded to previous treatment (refractory). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may induce changes in the body’s immune system, and may interfere with the ability of tumor cells to grow and spread.
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Project description:Purpose: More than 90% of children with diffuse intrinsic pontine glioma (DIPG) die within 2 years of diagnosis. There is a dire need to identify therapeutic targets, however lack of patient material for research has limited progress. We evaluated a large cohort of diffuse intrinsic pontine gliomas (DIPGs) to identify recurrent genomic abnormalities and gene expression signatures underlying DIPG. Patients and Methods: We used single nucleotide polymorphism arrays to evaluate genomic copy number imbalances in 43 DIPGs from 40 patients and in 8 low-grade exophytic brainstem gliomas. Gene expression arrays were used to evaluate expression signatures from 27 DIPGs, 6 low-grade exophytic brainstem gliomas and 66 low-grade gliomas arising outside the brainstem. Results: Frequencies of specific large-scale and focal imbalances varied significantly between DIPGs and pediatric glioblastomas outside the brainstem. Focal amplifications of genes within the receptor tyrosine kinase-Ras-PI3-kinase signaling pathway were found in 47% of DIPG, with PDGFRA and MET showing the highest frequency. 30% of DIPG contained focal amplifications of cell-cycle regulatory genes controlling RB phosphorylation, and 21% had concurrent amplification of genes from both pathways. Some tumors showed heterogeneity in amplification patterns. DIPGs showed distinct gene expression signatures relating to developmental processes compared to pediatric glioblastomas arising outside the brainstem, while expression signatures of low-grade exophytic brainstem gliomas were similar to low-grade gliomas outside the brainstem. Copy number analaysis: 43 DIPG samples, 8 Low Grade Gliomas using SNP6.0. Available matched normals are also profiled with SNP6.0. Expression analysis: 29 DIPG samples, 6 Low grade samples Please contact Suzanne Baker at Suzanne.Baker@stjude.org for CEL files and genotype calls.
2011-09-20 | E-GEOD-26576 | biostudies-arrayexpress
Project description:Genome-wide DNA methylation profiling of 10 pediatric bithalamic diffuse gliomas. The Illumina Infiunium 450k Human DNA Methylation Beadchip (n=4) or the Infinium EPIC 850k Human DNA Methylation Beadchip (n=6) was used to obtain DNA methylation profiles across approximately 450,000 or 850,000 CpG sites of genomic DNA extracted from formalin-fixed, paraffin-embedded tumor tissue of 10 pediatric bithalamic diffuse gliomas.
2020-04-19 | GSE140124 | GEO
Project description:Purpose: More than 90% of children with diffuse intrinsic pontine glioma (DIPG) die within 2 years of diagnosis. There is a dire need to identify therapeutic targets, however lack of patient material for research has limited progress. We evaluated a large cohort of diffuse intrinsic pontine gliomas (DIPGs) to identify recurrent genomic abnormalities and gene expression signatures underlying DIPG. Patients and Methods: We used single nucleotide polymorphism arrays to evaluate genomic copy number imbalances in 43 DIPGs from 40 patients and in 8 low-grade exophytic brainstem gliomas. Gene expression arrays were used to evaluate expression signatures from 27 DIPGs, 6 low-grade exophytic brainstem gliomas and 66 low-grade gliomas arising outside the brainstem. Results: Frequencies of specific large-scale and focal imbalances varied significantly between DIPGs and pediatric glioblastomas outside the brainstem. Focal amplifications of genes within the receptor tyrosine kinase-Ras-PI3-kinase signaling pathway were found in 47% of DIPG, with PDGFRA and MET showing the highest frequency. 30% of DIPG contained focal amplifications of cell-cycle regulatory genes controlling RB phosphorylation, and 21% had concurrent amplification of genes from both pathways. Some tumors showed heterogeneity in amplification patterns. DIPGs showed distinct gene expression signatures relating to developmental processes compared to pediatric glioblastomas arising outside the brainstem, while expression signatures of low-grade exophytic brainstem gliomas were similar to low-grade gliomas outside the brainstem.
2011-09-21 | GSE26576 | GEO
Project description:We have used Illumina Infinium HumanMethylation450 BeadChip array profiling to profile paediatric high grade gliomas and diffuse intrinsic pontine gliomas. The 450K methylation array is being used to separate brain tumour samples on the basis of their methylation profiles which represent the cell of origin the time and place in which tumours arise. Methylation arrays provide data for an integrated molecular diagnosis of brain tumours and define specific molecular subgroups and subtypes of high grade gliomas carrying distinct driver mutations and patterns of somatic alterations. These data form part of an integrated meta-analysis of high grade gliomas in children combining DNA copy number, methylation and high throughput sequencing datasets.
2017-09-28 | E-MTAB-5528 | biostudies-arrayexpress
Project description:Diffuse midline glioma (DMG) identifies gliomas originating in the thalami, brainstem, cerebellum and spine. Within this entity, tumours that infiltrate the pons, called diffuse intrinsic pontine gliomas (DIPGs), have a rapid onset and devastating neurological symptoms. Radiotherapy is the only intervention that is able to modify the disease course, albeit not in a curative way. In recent years, liquid biopsies have represented the next step in clinical diagnostics due to their easily accessible nature. The purpose of this study is to profile circulating miRNA expression to disclose a potential prognostic signature with clinical impact.
2022-12-21 | GSE160249 | GEO
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