NOTCH3 drives meningioma tumorigenesis and resistance to radiotherapy.

Meningiomas are the most common primary intracranial tumors ^1-3 . Treatments for patients with meningiomas are limited to surgery and radiotherapy, and systemic therapies remain ineffective or experimental ^4,5 . Resistance to radiotherapy is common in high-grade meningiomas ⁶ , and the cell types and signaling mechanisms driving meningioma tumorigenesis or resistance to radiotherapy are incompletely understood. Here we report NOTCH3 drives meningioma tumorigenesis and resistance to radiotherapy and find NOTCH3+ meningioma mural cells are conserved across meningiomas from humans, dogs, and mice. NOTCH3+ cells are restricted to the perivascular niche during meningeal development and homeostasis and in low-grade meningiomas but are expressed throughout high-grade meningiomas that are resistant to radiotherapy. Integrating single-cell transcriptomics with lineage tracing and imaging approaches across mouse genetic and xenograft models, we show NOTCH3 drives tumor initiating capacity, cell proliferation, angiogenesis, and resistance to radiotherapy to increase meningioma growth and reduce survival. An antibody stabilizing the extracellular negative regulatory region of NOTCH3 ^7,8 blocks meningioma tumorigenesis and sensitizes meningiomas to radiotherapy, reducing tumor growth and improving survival in preclinical models. In summary, our results identify a conserved cell type and signaling mechanism that underlie meningioma tumorigenesis and resistance to radiotherapy, revealing a new therapeutic vulnerability to treat meningiomas that are resistant to standard interventions.
Competing Interests: Competing interests statement AA is a co-founder of Tango Therapeutics, Azkarra Therapeutics, Ovibio Corporation, and Kytarro; a member of the board of Cytomx and Cambridge Science Corporation; a member of the scientific advisory board of Genentech, GLAdiator, Circle, Bluestar, Earli, Ambagon, Phoenix Molecular Designs, Yingli, ProRavel, Oric, Hap10, and Trial Library; a consultant for SPARC, ProLynx, Novartis, and GSK; receives research support from SPARC; and holds patents on the use of PARP inhibitors held jointly with AstraZeneca.