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Identification of diverse tumor endothelial cell populations in malignant glioma
- Source :
- Neuro Oncol
- Publication Year :
- 2020
- Publisher :
- Oxford University Press (OUP), 2020.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Cancer Research
Endothelium
Angiogenesis
Biology
medicine.disease_cause
03 medical and health sciences
0302 clinical medicine
Glioma
Tumor Microenvironment
medicine
Humans
Tumor microenvironment
Neovascularization, Pathologic
Brain Neoplasms
Endothelial Cells
Tumor-Derived
medicine.disease
Lymphangiogenesis
Editorial
030104 developmental biology
medicine.anatomical_structure
Oncology
Tumor progression
Cancer research
Neurology (clinical)
Carcinogenesis
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 15235866 and 15228517
- Volume :
- 23
- Database :
- OpenAIRE
- Journal :
- Neuro-Oncology
- Accession number :
- edsair.doi.dedup.....4404cc76004269a84ce307e2c924f474