An affinity for brainstem microglia in pediatric high-grade gliomas of brainstem origin

Liat Peretz Zats, Labiba Ahmad, Natania Casden, Meelim J. Lee, Vitali Belzer, Orit Adato, Shaked Bar Cohen, Seung Hyun B. Ko, Mariella G. Filbin, Ron Unger, Douglas A. Lauffenburger, Rosalind A. Segal, Oded Behar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background: High-grade gliomas (HGG) in children have a devastating prognosis and occur in a remarkable spatiotemporal pattern. Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), typically occur in mid-childhood, while cortical HGGs are more frequent in older children and adults. The mechanisms behind this pattern are not clear. Methods: We used mouse organotypic slice cultures and glial cell cultures to test the impact of the microenvironment on human DIPG cells. Comparing the expression between brainstem and cortical microglia identified differentially expressed secreted proteins. The impact of some of these proteins on DIPGs was tested. Results: DIPGs, pediatric HGGs of brainstem origin, survive and divide more in organotypic slice cultures originating in the brainstem as compared to the cortex. Moreover, brainstem microglia are better able to support tumors of brainstem origin. A comparison between the two microglial populations revealed differentially expressed genes. One such gene, interleukin-33 (IL33), is highly expressed in the pons of young mice and its DIPG receptor is upregulated in this context. Consistent with this observation, the expression levels of IL33 and its receptor, IL1RL1, are higher in DIPG biopsies compared to low-grade cortical gliomas. Furthermore, IL33 can enhance proliferation and clonability of HGGs of brainstem origin, while blocking IL33 in brainstem organotypic slice cultures reduced the proliferation of these tumor cells. Conclusions: Crosstalk between DIPGs and the brainstem microenvironment, in particular microglia, through IL33 and other secreted factors, modulates spatiotemporal patterning of this HGG and could prove to be an important future therapeutic target.

Original languageAmerican English
Article numbervdac117
JournalNeuro-Oncology Advances
Volume4
Issue number1
DOIs
StatePublished - 1 Jan 2022

Bibliographical note

Publisher Copyright:
© 2022 The Author(s). Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.

Keywords

  • DIPG
  • interleukin-33
  • microglia
  • pediatric high-grade gliomas

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