Meningioma is the most common primary brain tumor1,2. They occur more often in women and African Americans, each an underrepresented group in clinical trials. The current histopathological grading criteria3 fails to reliably predict the 20% of aggressive meningiomas3,4. To address this problem, we were the first group to use a multiplatform approach uncoupled from WHO criteria to identify three molecular groups (MenG A, B, and C) that better predict the risk of recurrence than the WHO system12. These groups can be identified using RNA sequencing, DNA methylation, or copy number analysis13. Over the past year, several independent groups have confirmed the validity of our three molecular group...

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Meningioma is the most common primary brain tumor1,2. They occur more often in women and African Americans, each an underrepresented group in clinical trials. The current histopathological grading criteria3 fails to reliably predict the 20% of aggressive meningiomas3,4. To address this problem, we were the first group to use a multiplatform approach uncoupled from WHO criteria to identify three molecular groups (MenG A, B, and C) that better predict the risk of recurrence than the WHO system12. These groups can be identified using RNA sequencing, DNA methylation, or copy number analysis13. Over the past year, several independent groups have confirmed the validity of our three molecular groups14-16. Two of these groups are NF2-deficient meningiomas with divergent clinical behavior: MenG B meningiomas, which are indolent, and MenG C meningiomas, which are aggressive. This proposal aims to understand what differentiates these types of tumors and identify the mechanisms that cause MenG C tumors to behave aggressively. MenG B tumors express the repressor form of the DREAM complex (a cell-cycle regulator), while MenG C tumors express the activator form. Our overarching hypothesis is that factors specific to MenG C tumor cells in the NF2 inactivation setting result in loss of DREAM repression and, in turn, unbridled cell proliferation. To test this, we will: (1) use single-cell sequencing to study (a) clonal evolution to understand how MenG C tumors develop and (b) molecular changes that occur during malignant progression; and (2) evaluate the regulatory pathways of the DREAM complex, in vitro and in vivo, using meningioma cell lines and our novel MenG C meningioma intracranial patient-derived xenograft (PDX) models19. Leveraging our large collection of human tumor samples, novel PDX models, and multi-disciplinary team, this study will increase our understanding of the biology of aggressive meningiomas and help identify potential therapeutic candidates.

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