NOTCH3 drives meningioma tumorigenesis and resistance to radiotherapy

Abrar Choudhury; Martha A Cady; Calixto-Hope G Lucas; Hinda Najem; Joanna J Phillips; Brisa Palikuqi; Naomi Zakimi; Tara Joseph; Janeth Ochoa Birrueta; William C Chen; Nancy Ann Oberheim Bush; Shawn L Hervey-Jumper; Ophir D Klein; Christine M Toedebusch; Craig M Horbinski; Stephen T Magill; Aparna Bhaduri; Arie Perry; Peter J Dickinson; Amy B Heimberger; Alan Ashworth; Elizabeth E Crouch; David R Raleigh

doi:10.1101/2023.07.10.548456

NOTCH3 drives meningioma tumorigenesis and resistance to radiotherapy

bioRxiv [Preprint]. 2023 Jul 11:2023.07.10.548456. doi: 10.1101/2023.07.10.548456.

Authors

Abrar Choudhury^{1

2

3

4}, Martha A Cady^{1

2

3

5}, Calixto-Hope G Lucas^{6

7}, Hinda Najem⁸, Joanna J Phillips^{2

3}, Brisa Palikuqi⁹, Naomi Zakimi^{1

2

3}, Tara Joseph¹⁰, Janeth Ochoa Birrueta¹⁰, William C Chen^{1

2

3}, Nancy Ann Oberheim Bush¹¹, Shawn L Hervey-Jumper², Ophir D Klein⁹, Christine M Toedebusch¹², Craig M Horbinski^{8

13}, Stephen T Magill⁸, Aparna Bhaduri¹⁴, Arie Perry^{2

3}, Peter J Dickinson¹², Amy B Heimberger⁸, Alan Ashworth^{15

16}, Elizabeth E Crouch^{10

17}, David R Raleigh^{1

2

3}

Affiliations

¹ Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.
² Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
³ Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
⁴ Medical Scientist Training Program, University of California San Francisco, San Francisco, CA, USA.
⁵ Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
⁶ Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
⁷ Department of Neurosurgery, Johns Hopkins University, Baltimore, MD, USA.
⁸ Department of Neurological Surgery, Northwestern University, Chicago, IL, USA.
⁹ Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA, USA.
¹⁰ Department of Pediatrics, University of California San Francisco, San Francisco, CA,USA.
¹¹ Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
¹² Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA, USA.
¹³ Department of Pathology, Northwestern University, Chicago, IL, USA.
¹⁴ Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, USA.
¹⁵ Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
¹⁶ Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
¹⁷ The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA.

Abstract

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 meningiomas⁶, 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.

Publication types

Preprint

Abstract

Publication types

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