Identification of diverse tumor endothelial cell populations in malignant glioma
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ABSTRACT:
PROVIDER: PRJNA666213 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12735620.fastq.gz | Fastqsanger.gz | |||
| SRR12735620_1.fastq.gz | Fastqsanger.gz | |||
| SRR12735620_2.fastq.gz | Fastqsanger.gz | |||
| SRR12735621_1.fastq.gz | Fastqsanger.gz | |||
| SRR12735621_2.fastq.gz | Fastqsanger.gz |
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Project description:Background: Glioblastoma multiform is the most common and aggressive type of primary brain tumor, as most patients succumb to the disease less than two years after their diagnosis. Critically, studies demonstrate that glioma recruits surrounding blood vessels, while some work suggests that tumor stem cells themselves may directly differentiate into endothelial cells, yet the molecular and cellular dynamics of the endothelium in glioma are poorly characterized. The goal of this study was to establish clear molecular and morphological benchmarks for tumor associated vessels (TAVs) and tumor derived endothelial cells (TDECs) during GBM disease progression. Methods: Using In-Utero Electroporation and CRISPR/Cas9 genome engineering to generate a native, immunocompetent mouse model of glioma, we characterized vascular-tumor dynamics in three dimensions during tumor progression. We also employed bulk and single-cell RNA-Sequencing to elucidate the relationship between TAV and TDECs. We confirmed our findings in a patient derived orthotopic xenograft (PDOX) model. Results: Using a mouse model of glioma, we identified progressive alteration of vessel function and morphogenesis over time. We also showed that TDECs exist, and that these cells contribute to vessels within the tumor. Furthermore, transcriptional profiling demonstrates that both TAVs and TDECs are molecularly distinct, and that both populations feature extensive molecular heterogeneity. Finally, the distinct molecular signatures of these heterogenous populations are also present in human glioma. Conclusions: Our findings show extensive endothelial cell heterogeneity within the tumor and tumor microenvironment, and provide insights into the diverse cellular and molecular mechanisms that drive glioma vascularization and angiogenesis during tumorigenesis.
2021-01-17 | GSE158700 | GEO
Project description:BackgroundGlioblastoma is the most common and aggressive type of primary brain tumor, as most patients succumb to the disease less than two years after diagnosis. Critically, studies demonstrate that glioma recruits surrounding blood vessels, while some work suggests that tumor stem cells themselves directly differentiate into endothelial cells, yet the molecular and cellular dynamics of the endothelium in glioma are poorly characterized. The goal of this study was to establish molecular and morphological benchmarks for tumor associated vessels (TAVs) and tumor derived endothelial cells (TDECs) during glioblastoma progression.MethodsUsing In-Utero Electroporation and CRISPR/Cas9 genome engineering to generate a native, immunocompetent mouse model of glioma, we characterized vascular-tumor dynamics in three dimensions during tumor progression. We employed bulk and single-cell RNA-Sequencing to elucidate the relationship between TAVs and TDECs. We confirmed our findings in a patient derived orthotopic xenograft (PDOX) model.ResultsUsing a mouse model of glioma, we identified progressive alteration of vessel function and morphogenesis over time. We also showed in our mouse model that TDECs are a rare subpopulation that contributes to vessels within the tumor, albeit to a limited degree. Furthermore, transcriptional profiling demonstrates that both TAVs and TDECs are molecularly distinct, and both populations feature extensive molecular heterogeneity. Finally, the distinct molecular signatures of these heterogeneous populations are also present in human glioma.ConclusionsOur findings show extensive endothelial heterogeneity within the tumor and tumor microenvironment and provide insights into the diverse cellular and molecular mechanisms that drive glioma vascularization and angiogenesis during tumorigenesis.
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Project description:Glioblastoma multiforme (GBM) is a highly aggressive and vascularized malignant brain tumor. Anti-VEGF therapy is widely used for the treatment of GBM, however it has shown only minor impact on patient survival. Thus, more precise molecular mechanisms for glioma angiogenesis are needed for the advance in the treatment of GBM. Here, we investigated gene expression profile of brain endothelial cells and glioma endothelial cells using RNA sequencing to validated special molecular features of glioma endothelial cells.
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Project description:Glioblastoma multiforme (GBM) is a highly aggressive and vascularized malignant brain tumor. SoxF transcription factors consisting of Sox7, Sox17, and Sox18 are expressed specifically in endothelial cells (ECs) and contribute to vascular morphogenesis. While the role of Sox17 was found in subcutaneous ectopic tumors, Sox7 has not been studied in the context of tumor angiogenesis. Here, we investigated gene expression profile of RNA analysis of Sox7- and Sox17-deficient mouse endothelial cells from high grade glioma using RNA sequencing to validate molecular characteristics of Sox7 and Sox17 in high grade glioma.
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Project description:As a starting point for dissecting the cellular heterogeneity of gliomas, different subpopulations from a CRISPR mouse model of glioma were profiled for gene expression. Because we initially identified these astrocyte subpopulations in the mouse brain, we first sought to determine whether their malignant analogues are present in mouse models of glioma. Towards this, we recently developed a mouse model of malignant glioma, one that utilizes E16.5 IUE approaches in combination with CRISPR mediated gene editing, where we use IUE to introduce gRNA vectors to delete NFI, PTEN, and p53, CAS9, and a GFP reporter, resulting in the generation of malignant glioma at P70. Using the GFP label to distinguish tumor from normal brain tissue, along with FACS-based selection against the glioma stem cell (GSC) and endothelial cells (see methods), we screened our tumor models for the presence of these prospective astroglial populations in the non-GSC fractions of these tumors.
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