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

Peretz Zats, L.; Ahmad, L.; Casden, N.; Lee, M. J.; Belzer, V.; Adato, O.; Bar-Cohen, S.; Ko, S.-H. B.; Filbin, M. G.; Unger, R.; Lauffenburger, D. A.; Segal, R.; Behar, O.

doi:10.1101/2022.06.15.496357

bioRxiv · 10.1101/2022.06.15.496357

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

Peretz Zats, L.·Ahmad, L.·Casden, N.·Lee, M. J.·Belzer, V.·Adato, O.·Bar-Cohen, S.·Ko, S.-H. B.·Filbin, M. G.·Unger, R.·Lauffenburger, D. A.·Segal, R.·Behar, O.

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Abstract

BackgroundHigh-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. MethodsWe 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. ResultsDIPGs, 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. ConclusionsCrosstalk 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. Key PointsO_LIDIPGs divide more in the brainstem environment compared to the cortex. C_LIO_LIIL33 expression in brainstem and brainstem microglia is higher than in the cortex of young mice. C_LIO_LIIL33 propagates DIPG tumorigenesis, and its inhibition decreases DIPG proliferation. C_LI Importance of the StudyPediatric gliomas can arise in the supratentorial cerebral cortex with a median diagnosis age of 13 years, while diffuse midline gliomas (DMGs), present a median diagnosis age of 7 years, and appear most frequently in the pons. DMGs have a devastating prognosis and are currently untreatable. We tested the contribution of the brainstem microenvironment to the observed spatiotemporal pattern of pediatric HGGs. Our results support a model in which the brainstem microenvironment, particularly microglia, offers more supportive conditions for DIPG cells. By using the differences in gene expression between brainstem and cortical microglia we were able to identify factors that may contribute to the DIPG preference toward the brainstem. In this study we focused on the factor IL33, and provided evidence to support its contribution to the propagation of DIPGs in this specific anatomical location.

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Peretz Zats, L., Ahmad, L., Casden, N., Lee, M. J., Belzer, V., Adato, O., Bar-Cohen, S., Ko, S.-H. B., Filbin, M. G., Unger, R., Lauffenburger, D. A., Segal, R., Behar, O.. 2022-06-17. An affinity for brainstem microglia in pediatric high grade gliomas of brainstem origin. https://doi.org/10.1101/2022.06.15.496357

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