Gene expression profile at single cell levels of post natal day 7 mouse cerebellar subdural meningeal cells
The microenvironment exerts a profound control on tumor initiation in many tissues.  In brain tumors, this process is under studied, in particular how stromal signals exert effects on cancer signaling in pre-tumor cells.  In the cerebellum, canonical Wnt signalling mediated by Norrin/Frizzled4 (Fzd4) activation in endothelial cells in the meninges exerts a potent inhibitory effect on preneoplasia and tumour progression in mouse models of Sonic hedgehog medulloblastoma (Shh-MB). Single cell transcriptome profiling and deep phenotyping of the meninges during the critical period of preneoplasia development revealed that Norrin/Fzd4 signalling maintains the activation of meningeal macrophages (mMFs), characterized by Lyve1 and CXCL4 expression. mMF depletion during this critical period phenocopies the enhanced preneoplasia and tumourigenesis caused by Ndp loss. CXCL4 mediates the anti-tumourigenesis effect of mMFs, as it antagonizes CXCL12/CXCR4 signaling in granule neuron progenitors, the MB cell of origin, to reduce cell cycle progression and promote migration away from the pre-tumour niche. Taken together, these findings are the first demonstration that mMFs are key mediators of chemokine-regulated anti-cancer cross talk between the stroma and pre-tumour cells in the control of MB initiation. Overall design: Primary subdural meningeal cells were from NdpWT; SmoA1+/- and NdpKO; SmoA1+/- from perinatal mice (C57/BL6 background) at age P6-P8 and dissociated and analyzed using scRNASeq.