Multiomic Characterization of Meningiomas Informs Cell of Origin and Identifies Immune Dysregulation at the Blood-CSF Barrier

Meningiomas represent 1/3 of adult brain tumors and arise from the meninges, a layered immune organ that forms the blood CSF-barrier. While molecular characterization has revolutionized our capacity to distinguish benign from aggressive tumors, the developmental relationship between meningiomas and the specialized layers of the meninges remains underexplored. Using single cell transcriptomics, we identify layer-specific signatures in individual meningiomas raising the intriguing possibility that the histologic and clinical diversity of meningiomas is influenced by cell of origin. Invasive tumors were transcriptionally similar to pia and exhibited an infiltrating subpopulation of myelinating cells implicating a reactivation of developmental mechanisms in the pathogenesis of invasion. Immune cells constituted ~ 1/3 of cells in a tumor, most of which were SPI1  + tissue resident border macrophages while MYB+ bone-marrow derived macrophages were lacking. WHO I meningiomas were infiltrated with LYVE1  + border macrophages while macrophages in grade II meningiomas expressed PTGDS . Estimation of immune cell composition in meningiomas profiled by DNA methylation arrays identified characteristic immune signatures of prognostically significant molecular categories of meningiomas and a previously unrecognized level of epigenetic diversity in grade 2/3 meningiomas. Meningiomas may arise from multiple layers of the meninges rather than just arachnoid cap cells with implications for clinical behavior.