Perivascular NOTCH3+ Stem Cells Drive Meningioma Tumorigenesis and Resistance to Radiotherapy

Abstract Meningiomas are the most common primary intracranial tumors. Treatments for patients with meningiomas are limited to surgery and radiotherapy, and systemic therapies remain ineffective or experimental. Resistance to radiotherapy is common in high-grade meningiomas and the cell types and signaling mechanisms that drive meningioma tumorigenesis and resistance to radiotherapy are incompletely understood. Here, we report that NOTCH3 drives meningioma tumorigenesis and resistance to radiotherapy and find that perivascular NOTCH3+ stem cells are conserved across meningiomas from humans, dogs, and mice. Integrating single-cell transcriptomics with lineage tracing and imaging approaches in genetically engineered mouse models and xenografts, we show NOTCH3 drives tumor-initiating capacity, cell proliferation, angiogenesis, and resistance to radiotherapy to increase meningioma growth and reduce survival. To translate these findings to patients, we show that an antibody stabilizing the extracellular negative regulatory region of NOTCH3 blocks meningioma tumorigenesis and sensitizes meningiomas to radiotherapy, reducing tumor growth and improving survival. Significance: There are no effective systemic therapies to treat meningiomas, and meningioma stem cells are poorly understood. Here, we report perivascular NOTCH3+ stem cells to drive meningioma tumorigenesis and resistance to radiotherapy. Our results identify a conserved mechanism and a therapeutic vulnerability to treat meningiomas that are resistant to standard interventions.