Identification of diverse tumor endothelial cell populations in malignant glioma

Abstract

Background Glioblastoma 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 GBM 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 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 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 heterogenous populations are also present in human glioma. Conclusions Our 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.

Tumor Vessels Fuel the Fire in Glioblastoma

“…Indeed, TDECs are resistant to anti-VEGF therapies, which even increase their frequency [ 147 ]. Recently, it has been shown that TDECs differ from tumor-associated vessels and compose molecularly distinct populations [ 149 ].…”

Coaxially Bioprinted Cell-Laden Tubular-Like Structure for Studying Glioma Angiogenesis

“…An important characteristic of GBM is the abundance of abnormal vascular systems, and this uncontrolled vascular growth plays a crucial role in the occurrence, progression, and invasion of tumor (Carlson et al, 2020). Elucidating and understanding the molecular mechanism of tumor angiogenesis is very important for the targeted therapy of antitumor angiogenesis.…”

Circular RNA: A novel type of biomarker for glioma (Review)

“…Several of these angiogenic members are signaling proteins that couple with stimulating or suppressive cell surface receptors exhibited by vascular endothelial cells. In addition, glial vascular endothelial cells may excrete a considerable quantity of factors that accelerate cancer development ( 98 ). Notably, research has shown that circRNAs can regulate the interactions of these secreted factors to induce angiogenesis.…”

“…circRNAs may regulate the interactions of pro-angiogenic factors and glioma growth factors to induce angiogenesis. Angiogenesis is the basis of hematogenous metastasis in glioma and new blood vessels have been characterized as essential channels for glioma to transport nutrients ( 97 , 98 ). These circRNA studies may be useful in designing approaches to improving the survival of patients with glioma.…”