Perivascular NOTCH3+ stem cells drive meningioma tumorigenesis and resistance to radiotherapy.
Abrar ChoudhuryMartha A CadyCalixto-Hope G LucasHinda NajemJoanna J PhillipsBrisa PalikuqiNaomi ZakimiTara JosephJaneth Ochoa BirruetaWilliam C ChenNancy Ann Oberheim BushShawn L Hervey-JumperOphir D KleinChristine M ToedebuschCraig M HorbinskiStephen T MagillAparna BhaduriArie PerryPeter J DickinsonAmy B HeimbergerAlan AshworthElizabeth E CrouchDavid R RaleighPublished in: Cancer discovery (2024)
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 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.
Keyphrases
- early stage
- cell proliferation
- locally advanced
- single cell
- stem cells
- radiation induced
- radiation therapy
- optic nerve
- high grade
- minimally invasive
- rectal cancer
- cell therapy
- end stage renal disease
- newly diagnosed
- high resolution
- chronic kidney disease
- cell cycle
- endothelial cells
- ejection fraction
- high throughput
- mass spectrometry
- acute coronary syndrome
- coronary artery bypass
- peritoneal dialysis
- metabolic syndrome
- patient reported outcomes
- prognostic factors
- signaling pathway
- adipose tissue
- vascular endothelial growth factor
- free survival