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This review reflects comments and contributions from Marta Oliva Santiago & Femi Arogundade. Review synthesized by Arpita Ghosh and Garima Jain.

The study investigates the role of NOTCH3 in driving the tumorigenesis of meningiomas and their resistance to radiotherapy, highlighting potential therapeutic avenues for treating these tumors. The research encompasses human, dog, and mouse models, uncovering the involvement of NOTCH3 in angiogenesis, cancer stem cell properties, and its relevance across various meningioma grades and molecular groups. The study suggests that NOTCH3 inhibition could be a promising strategy for addressing meningiomas resistant to standard treatments, presenting an opportunity for further research and potential clinical applications.

Major comments:

• The study reports that NOTCH3 plays a critical role in driving the formation of meningiomas and their resistance to radiotherapy. This phenomenon is observed in various cell types across humans, dogs, and mice.

• The study employs various molecular and genetic techniques to understand the role of NOTCH3 in meningioma development and resistance to therapy. It highlights the potential for NOTCH3 as a therapeutic target and emphasizes the need for further research and clinical testing to validate these findings in human patients.

• The findings suggest that targeting NOTCH3 could be a new therapeutic strategy to treat meningiomas that do not respond to standard treatments. This could be a significant breakthrough for a common intracranial tumor.

• The study indicates that the vasculature in meningiomas is composed of both endothelial cells from the microenvironment and tumor cells. NOTCH3 signaling between these mural cells and endothelial cells appears to contribute to meningioma migration into surrounding tissues. This migration pattern could explain why some meningiomas recur after standard treatments.

• NOTCH3+ meningioma mural cells exhibit characteristics of cancer stem cells, such as promoting cell proliferation, clonogenic growth, angiogenesis, and resistance to treatment. This highlights the significance of NOTCH3 in meningioma pathogenesis.

• The study acknowledges that other stem or progenitor cells might contribute to meningioma tumorigenesis, especially in meningiomas with intact NF2. The presence of PTGDS cells is mentioned, suggesting heterogeneity in meningioma stem cells.

• NOTCH3 and NOTCH3 target genes are enriched in high-grade and recurrent meningiomas. However, NOTCH3 signaling and NOTCH3+ cells are identified in meningiomas across all grades and molecular groups.

• While the safety and efficacy of NOTCH3 inhibition in humans have not been defined, the study suggests that it could be a promising systemic therapy for treating resistant meningiomas, as Notch3 knockout mice are viable and fertile.

Minor comments:

• How were the human meningioma tissue samples collected and characterized? Were there any specific criteria for the selection of samples, such as tumor grade or molecular subtypes?

• What were the specific details of the radiation therapy administered to the experimental models, including the dose, duration, and fractionation scheme?

• How was the resistance to radiotherapy assessed and quantified in the study?

• What assays or experiments were conducted to elucidate the mechanisms by which NOTCH3 drives tumorigenesis in meningiomas?

• How were NOTCH3-positive mural cells' cancer stem cell characteristics determined and characterized?

• How were the angiogenic properties of NOTCH3+ mural cells and their interactions with endothelial cells assessed and quantified? Were there any additional factors involved in this process that were not discussed in the study?

• How was patient data integrated with the experimental findings to make the connections between NOTCH3 expression, tumor aggressiveness, and clinical outcomes? Were any specific clinical or genetic factors considered in this integration?

• What specific therapeutic approaches could be developed based on the findings in this study, and what is their potential impact on patient outcomes?

• The study mentions that the safety and efficacy of selective NOTCH3 inhibition have not been defined in humans. What would be the next steps in terms of preclinical and clinical trials to assess the safety and efficacy of NOTCH3 inhibition in treating meningiomas? Are there any potential side effects or risks associated with targeting NOTCH3 that need to be investigated?

Comments on reporting:

• The paper contains extensive information, and it would be beneficial to summarize the key findings in the discussion section, emphasizing the clinical and biological implications of the results.

Suggestions for future studies:

• Perform high-throughput drug screening to identify potential therapeutic agents that can target specific pathways identified in this study. Developing targeted therapies that can overcome NOTCH3-mediated resistance to radiotherapy could be a significant breakthrough.

• Investigate the role of other genetic and epigenetic alterations in meningioma development. This could include whole-genome sequencing, epigenome mapping, and transcriptome profiling to identify additional genetic and epigenetic drivers of meningioma progression.

• Investigate the potential of immunotherapy in treating meningiomas. Understanding the immune microenvironment in these tumors and exploring immunotherapeutic strategies, such as immune checkpoint inhibitors or tumor-infiltrating lymphocyte therapies, could be promising.

• Conduct prospective, large-scale clinical studies to validate the findings of this preprint in a broader patient population. This would help determine the clinical relevance of NOTCH3 as a therapeutic target and resistance factor for radiotherapy.

• Undertake long-term follow-up studies of meningioma patients to assess the recurrence rates, survival outcomes, and late effects of radiotherapy, especially in cases involving NOTCH3 mutations. This will provide insights into the clinical relevance and long-term consequences of therapy resistance.

• Identify and validate predictive biomarkers for therapy response and resistance. Understanding which patients are more likely to benefit from specific treatments can help personalize therapeutic strategies.

• Explore the possibility of molecular subtyping of meningiomas to tailor treatment strategies. Different meningioma subtypes may have distinct genetic profiles and responses to therapy.

• Assess patient-reported outcomes and quality of life in long-term meningioma survivors, particularly those who have received radiotherapy. This can provide valuable insights into the patient experience and guide treatment decisions.

Competing interests

The author declares that they have no competing interests.