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 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.
Overview
- The study investigates the role of NOTCH3 in meningioma tumorigenesis and resistance to radiotherapy. The study uses single-cell transcriptomics, lineage tracing, and imaging approaches in genetically engineered mouse models and xenografts to understand the mechanisms underlying meningioma growth and resistance to radiotherapy. The study aims to identify potential therapeutic targets for meningiomas, which are limited to surgery and radiotherapy. The hypothesis being tested is that NOTCH3 drives meningioma tumorigenesis and resistance to radiotherapy and that an antibody stabilizing the extracellular negative regulatory region of NOTCH3 can block meningioma tumorigenesis and sensitize meningiomas to radiotherapy. The study uses human, dog, and mouse meningiomas for comparison. The methodology used for the experiment includes single-cell transcriptomics, lineage tracing, imaging approaches, and genetically engineered mouse models and xenografts. The primary objective of the study is to identify potential therapeutic targets for meningiomas and to develop a new treatment strategy for this disease.
Comparative Analysis & Findings
- The study compares the outcomes observed under different experimental conditions or interventions, including single-cell transcriptomics, lineage tracing, imaging approaches, and genetically engineered mouse models and xenografts. The study identifies that NOTCH3 drives meningioma tumorigenesis and resistance to radiotherapy. The study also shows that perivascular NOTCH3+ stem cells are conserved across meningiomas from humans, dogs, and mice. The study finds that NOTCH3 drives tumor initiating capacity, cell proliferation, angiogenesis, and resistance to radiotherapy to increase meningioma growth and reduce survival. The study also shows 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. The study identifies that NOTCH3 is a potential therapeutic target for meningiomas and that an antibody stabilizing the extracellular negative regulatory region of NOTCH3 can be used as a new treatment strategy for this disease.
Implications and Future Directions
- The study's findings have significant implications for the field of research and clinical practice. The study identifies that NOTCH3 drives meningioma tumorigenesis and resistance to radiotherapy and that an antibody stabilizing the extracellular negative regulatory region of NOTCH3 can be used as a new treatment strategy for this disease. The study also identifies that perivascular NOTCH3+ stem cells are conserved across meningiomas from humans, dogs, and mice, which could be used as a model for studying meningioma tumorigenesis and resistance to radiotherapy. The study suggests that future research could focus on developing new antibodies or therapies targeting NOTCH3 to treat meningiomas. The study also suggests that future research could focus on understanding the role of perivascular NOTCH3+ stem cells in meningioma tumorigenesis and resistance to radiotherapy. The study highlights the importance of understanding the mechanisms underlying meningioma growth and resistance to radiotherapy to develop new treatment strategies for this disease.