Wasl is crucial to maintain microglial core activities during glioblastoma initiation stages

Microglia actively promotes the growth of high-grade gliomas. Within the glioma microenvironment an amoeboid microglial morphology has been observed, however the underlying causes and the related impact on microglia functions and their tumor promoting activities is unclear. Using the advantages of the larval zebrafish model, we identified the underlying mechanism and show that microglial morphology and functions are already impaired during glioma initiation stages. The presence of pre-neoplastic HRasV12 expressing cells induces an amoeboid morphology of microglia, increases microglial numbers and decreases their motility and phagocytic activity. RNA sequencing analysis revealed lower expression levels of the actin nucleation promoting factor wasla in microglia. Importantly, a microglia specific rescue of wasla expression restores microglial morphology and functions. This results in increased phagocytosis of pre-neoplastic cells and slows down tumor progression. In conclusion, we identified a mechanism that de-activates core microglial functions within the emerging glioma microenvironment. Restoration of this mechanism might provide a way to impair glioma growth.

Automated summary

This study reveals that microglia plays an active role in promoting the growth of high-grade gliomas. Using the larval zebrafish model, the researchers found that microglial morphology and functions are impaired during glioma initiation stages. Further analysis showed that the presence of pre-neoplastic cells induces an amoeboid morphology in microglia, reduces their motility and phagocytic activity, and downregulates the expression of the actin nucleation promoting factor wasla. Importantly, restoring the expression of wasla in microglia restores their morphology and functions, leading to increased phagocytosis of pre-neoplastic cells and slower tumor progression.