UCSF

Meningiomas arising from the meningothelial lining of the central nervous system are the most common primary intracranial tumors, and a significant cause of neurologic morbidity and mortality. There are no effective medical therapies for meningioma patients, and new treatments have been encumbered by limited understanding of meningioma biology. DNA methylation profiling provides robust classification of brain tumors, but has not informed new treatments for patients.

Here we use DNA methylation profiling on 565 meningiomas, controlled for confounding artifacts from copy number variants and integrated with genetic, transcriptomic, biochemical, and single-cell approaches, to show meningiomas are comprised of 3 groups with distinct clinical outcomes, biological drivers, and therapeutic vulnerabilities. Merlin-intact meningiomas have the best outcomes and are distinguished by NF2/Merlin regulation of glucocorticoid signaling and apoptosis. Immune-enriched meningiomas have intermediate outcomes and are distinguished by immune infiltration, HLA expression, and lymphatic vessels. Hypermitotic meningiomas have the worst outcomes and are distinguished by convergent genetic mechanisms misactivating the cell cycle. Translating these findings, we show cell cycle inhibitors block Immune-enriched and Hypermitotic meningioma growth in cell culture, organoids, xenografts, and patients.

To extend the relevance of our findings, we use single-cell RNA sequencing of 8 human meningiomas, 3 canine meningiomas, and 1 human hemangiopericytoma to identify Notch3+ perivascular cells as a potential cell of origin for meningeal tumors. This perivascular cell population is conserved across meningeal tumors in both humans and canines and across normal meningeal tissue in both humans and mice. These findings set the stage for developing new mouse models of meningioma, which will accelerate and enhance our ability to study meningioma biology, such as interrogating the pathways and phenotypes identified from DNA methylation groups. Moreover, new mouse models will also allow us to study meningiomas in the context of the immune system and test the efficacy of drugs in a more physiologic setting. Our results establish a framework for understanding meningioma biology, provide the basis for new meningioma treatments, and lay the foundation for future meningioma studies.