Regional heterogeneity of glioblastoma upon single-cell RNA sequencing
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE188772 | GEO | 2022/01/15
REPOSITORIES: GEO
Similar Datasets
Project description:Glioblastoma (GBM) remains an untreatable disease. Understanding of GBM’s infiltrative biology at the resection margin is limited, despite causing disease recurrence and progression. To address this, we generated a high-throughput single-nucleus (sn)RNA-seq and snATAC-seq multi-omic dataset from six tumors with distinct genomic drivers and combined it with spatial transcriptomics to characterize the unique molecular phenotype of GBM near the margin. By contrasting GBM-specific biology in matching “Core” vs. “Margin” dissections, we define unique, shared “GBM infiltration” and chromatin accessibility signatures near the margin. We prioritize EGFR as a top differentially expressed and accessible “Margin” marker across GBM subtypes, show its dynamic expression along a core-to-margin infiltration trajectory, and validate its role in migration through CRISPR/Cas9 deletion in two patient-derived models. ChIP-seq studies furthermore corroborate preferential TEAD1 binding at EGFR’s accessible regulatory elements. This validated multi-omic dataset enables further studies into tumor and microenvironment biology in the context of residual GBM disease.
2025-07-14 | GSE286415 | GEO
Project description:Glioblastoma (GBM) remains an untreatable disease. Understanding of GBM’s infiltrative biology at the resection margin is limited, despite causing disease recurrence and progression. To address this, we generated a high-throughput single-nucleus (sn)RNA-seq and snATAC-seq multi-omic dataset from six tumors with distinct genomic drivers and combined it with spatial transcriptomics to characterize the unique molecular phenotype of GBM near the margin. By contrasting GBM-specific biology in matching “Core” vs. “Margin” dissections, we define unique, shared “GBM infiltration” and chromatin accessibility signatures near the margin. We prioritize EGFR as a top differentially expressed and accessible “Margin” marker across GBM subtypes, show its dynamic expression along a core-to-margin infiltration trajectory, and validate its role in migration through CRISPR/Cas9 deletion in two patient-derived models. ChIP-seq studies furthermore corroborate preferential TEAD1 binding at EGFR’s accessible regulatory elements. This validated multi-omic dataset enables further studies into tumor and microenvironment biology in the context of residual GBM disease.
2025-07-14 | GSE286413 | GEO
Project description:Glioblastoma (GBM) remains an untreatable disease. Understanding of GBM’s infiltrative biology at the resection margin is limited, despite causing disease recurrence and progression. To address this, we generated a high-throughput single-nucleus (sn)RNA-seq and snATAC-seq multi-omic dataset from six tumors with distinct genomic drivers and combined it with spatial transcriptomics to characterize the unique molecular phenotype of GBM near the margin. By contrasting GBM-specific biology in matching “Core” vs. “Margin” dissections, we define unique, shared “GBM infiltration” and chromatin accessibility signatures near the margin. We prioritize EGFR as a top differentially expressed and accessible “Margin” marker across GBM subtypes, show its dynamic expression along a core-to-margin infiltration trajectory, and validate its role in migration through CRISPR/Cas9 deletion in two patient-derived models. ChIP-seq studies furthermore corroborate preferential TEAD1 binding at EGFR’s accessible regulatory elements. This validated multi-omic dataset enables further studies into tumor and microenvironment biology in the context of residual GBM disease.
2025-07-14 | GSE286419 | GEO
Project description:Glioblastoma (GBM) is an aggressive form of brain cancer with well-established patterns of intra-tumoral heterogeneity implicated in treatment resistance, recurrence and progression. While regional and single cell transcriptomic variations of GBM have been recently resolved, downstream phenotype-level proteomic programs have yet to be assigned to specific niches. Here, we leverage mass spectrometry to spatially align abundance levels of 4,794 proteins to GBM’s hallmark histomorphologic niches across 20 patients and define distinct molecular programs operational within these regional tumor compartments. Using machine learning, we overlay concordant transcriptional information, and define two distinct proteogenomic programs, MYC- and KRAS-axis hereon, that cooperate with hypoxia to produce a tri-dimensional model of intra-tumoral heterogeneity. Importantly, we show using multiple cohorts, that GBMs with an enhanced KRAS component harbor a more clinically aggressive and infiltrative phenotype. Conversely, tumor cells enriched along the MYC axis where mutually exclusive and had a distinct proliferative program. Moreover, by applying both experimental and computational approaches to link each of these distinct molecular axes with potential pharmacological therapies, we highlight differential drug sensitivities and a notable relative chemoresistance in GBM cell lines with enhanced KRAS programs. Importantly, pharmacological differences were less evident when using traditional expression-based subgroups supporting thattopographic phenotypic mapping ofGBM, and the proposed axes may provide new insights for targeting heterogeneity and overcoming therapy resistance in this aggressive disease.
2021-11-02 | PXD029290 | Pride
Project description:Regional heterogeneity of glioblastoma upon single-cell RNA sequencing
| PRJNA796656 | ENA
Project description:Isocitrate dehydrogenase wild type glioblastoma (GBM) is an aggressive brain tumour characterized by rapid growth and infiltration into adjacent functional brain tissue. Presently, treatment is restricted to surgical resection followed by temozolomide chemotherapy and concomitant radiotherapy; however, new therapies are desperately needed to improve GBM patient outcome. Intra-tumoural heterogeneity is a common driver of failure for novel GBM treatments, and many preclinical studies rely on cell lines established from the tumour core. As a result, they fail to characterise the infiltrative cells which remain post-surgery and ultimately drive tumour recurrence. This study characterises the membrane proteome of 3 patient-derived GBM cell lines isolated from the tumour infiltrative margin (GIN8, GIN28, and GIN31), which are a proxy for residual disease post-surgery.
2026-09-07 | PXD058999 | Pride
Project description:Extensive neovascularization is a hallmark of glioblastoma (GBM). In addition to supplying oxygen and nutrients, vascular endothelial cells provide trophic support to GBM cells via paracrine signaling. Here we report that Endocan (ESM1), an endothelial-secreted proteoglycan, confers enhanced proliferative, migratory, and angiogenic properties to GBM cells and regulates their spatial identity. Mechanistically, Endocan exerts at least part of its functions via direct binding and activation of the PDGFRA receptor. Subsequent downstream signaling enhances chromatin accessibility of the Myc promoter and upregulates Myc expression inducing stable phenotypic changes in GBM cells. Furthermore, Endocan confers a radioprotection phenotype in GBM cells, both in vitro and in vivo. Inhibition of Endocan-PDGFRA signaling with ponatinib increases survival in the Esm1 wild-type but not in the Esm1 knock-out mouse GBM model. Our findings identify Endocan and its downstream signaling axis as a potential target to subdue GBM recurrence and highlight the importance of vascular-tumor interactions for GBM development.
2024-12-04 | PXD057635 | Pride
Project description:The purpose of this study is to determine whether the combination of two agents, INC280 and bevacizumab, is safe and effective when administered to patients with Glioblastoma Multiforme (GBM) who have progressed after receiving prior therapy or who have unresectable GBM.
| 2185625 | ecrin-mdr-crc
Project description:The reaction of quiescent tumor cell subpopulations at the invasive margin of glioblastoma (GBM) might be cleared by immune surveillance toward death or expand through immune escape, which can drive therapeutic resistance, tumor dissemination, and recurrence through phenotypic plasticity. However, the process and mechanisms underlying their activation remain largely unclear. This study revealed that astrocytes awaken quiescent GBM cells to cycling and immune-evasive phenotypes. Astrocytic mitochondria are indispensable in regulating the phenotypic changes. Specifically, the SHMT2 enzyme in astrocytic mitochondria catalyzes one-carbon metabolic products, which significantly promote synthetic metabolic activation and reactivation of quiescent GBM cells to immune evasion through intercellular mitochondrial transfer. Tumor cells that acquire astrocytic mitochondria enhanced one-carbon metabolism drives global hyperactive anabolic metabolism through YTHDC1-mediated transcriptional pause release of ribosomal and focal adhesion signaling genes, supporting rapid proliferation and conferring a potent immune-evasive phenotype. Therapeutically, pharmacologic or genetic inhibiting the astrocytic SHMT2 or blocking mitochondrial transfer markedly suppressed quiescent GBM cell activation and tumor progression. These findings elucidate a novel mechanism by which astrocytes in the tumor microenvironment drive GBM malignancy through metabolic symbiosis.
2026-07-30 | PXD073573 | Pride
Project description:The reaction of quiescent tumor cell subpopulations at the invasive margin of glioblastoma (GBM) might be cleared by immune surveillance toward death or expand through immune escape, which can drive therapeutic resistance, tumor dissemination, and recurrence through phenotypic plasticity. However, the process and mechanisms underlying their activation remain largely unclear. This study revealed that astrocytes awaken quiescent GBM cells to cycling and immune-evasive phenotypes. Astrocytic mitochondria are indispensable in regulating the phenotypic changes. Specifically, the SHMT2 enzyme in astrocytic mitochondria catalyzes one-carbon metabolic products, which significantly promote synthetic metabolic activation and reactivation of quiescent GBM cells to immune evasion through intercellular mitochondrial transfer. Tumor cells that acquire astrocytic mitochondria enhanced one-carbon metabolism drives global hyperactive anabolic metabolism through YTHDC1-mediated transcriptional pause release of ribosomal and focal adhesion signaling genes, supporting rapid proliferation and conferring a potent immune-evasive phenotype. Therapeutically, pharmacologic or genetic inhibiting the astrocytic SHMT2 or blocking mitochondrial transfer markedly suppressed quiescent GBM cell activation and tumor progression. These findings elucidate a novel mechanism by which astrocytes in the tumor microenvironment drive GBM malignancy through metabolic symbiosis.
2026-07-30 | PXD073278 | Pride