Defining tumor-associated vascular heterogeneity in pediatric high-grade and diffuse midline gliomas

Xin Wei,Marjolein Breur,Marianna Bugiani,Esther Hulleman,Michaël H Meel,Timothy N Phoenix

doi:10.1186/s40478-021-01243-1

Abstract

The blood–brain barrier (BBB) plays important roles in brain tumor pathogenesis and treatment response, yet our understanding of its function and heterogeneity within or across brain tumor types remains poorly characterized. Here we analyze the neurovascular unit (NVU) of pediatric high-grade glioma (pHGG) and diffuse midline glioma (DMG) using patient derived xenografts and natively forming glioma mouse models. We show tumor-associated vascular differences between these glioma subtypes, and parallels between PDX and mouse model systems, with DMG models maintaining a more normal vascular architecture, BBB function and endothelial transcriptional program relative to pHGG models. Unlike prior work in angiogenic brain tumors, we find that expression of secreted Wnt antagonists do not alter the tumor-associated vascular phenotype in DMG tumor models. Together, these findings highlight vascular heterogeneity between pHGG and DMG and differences in their response to alterations in developmental BBB signals that may participate in driving these pathological differences.

Highlights

The blood–brain barrier (BBB) is a specialized vascular structure within the brain formed by the neurovascular unit (NVU) which consists of endothelial cells, pericytes, astrocytes and neurons [1]
diffuse midline glioma (DMG) patient-derived xenograft (PDX) blood vessels showed no noticeable differences in the expression or organization of Glut1 and Cldn5 compared to normal brain regions (Fig. 1c)
We show that the vascular network within DMGs remains mostly intact with respect to blood vessel morphology, Blood brain barrier (BBB) function and transcriptional programs, while cortical pediatric high-grade glioma (pHGG) display both phenotypic and transcriptional changes related to disorganized angiogenesis, inflammation and BBB dysfunction (Fig. 8)

Summary

Introduction

The blood–brain barrier (BBB) is a specialized vascular structure within the brain formed by the neurovascular unit (NVU) which consists of endothelial cells, pericytes, astrocytes and neurons [1]. BBB function was historically considered disrupted in brain tumors based on studies using aggressive adult glioma models that do not accurately reflect the diversity and pathological heterogeneity identified. Pediatric high-grade gliomas (pHGGs) are among the most common childhood brain tumors and can be divided into multiple subgroups based different features including histology, location, mutation status and molecular profile [5,6,7,8]. One proposed reason for the failure of systemically delivered therapies is that DMGs maintains a more intact BBB compared to other non-brainstem tumors, as clinicians have noted that DMGs frequently display little to no contrast enhancement on magnetic resonance imaging (MRI) [11, 12]. A detailed characterization or direct comparison of tumor-associated vasculature in cortical pHGGs and DMGs has not been systematically performed

Methods

Results

Conclusion