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NOTCH3 drives meningioma tumorigenesis and resistance to radiotherapy.
Choudhury, Abrar; Cady, Martha A; Lucas, Calixto-Hope G; Najem, Hinda; Phillips, Joanna J; Palikuqi, Brisa; Zakimi, Naomi; Joseph, Tara; Birrueta, Janeth Ochoa; Chen, William C; Bush, Nancy Ann Oberheim; Hervey-Jumper, Shawn L; Klein, Ophir D; Toedebusch, Christine M; Horbinski, Craig M; Magill, Stephen T; Bhaduri, Aparna; Perry, Arie; Dickinson, Peter J; Heimberger, Amy B; Ashworth, Alan; Crouch, Elizabeth E; Raleigh, David R.
Afiliação
  • Choudhury A; Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.
  • Cady MA; Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
  • Lucas CG; Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
  • Najem H; Medical Scientist Training Program, University of California San Francisco, San Francisco, CA, USA.
  • Phillips JJ; Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.
  • Palikuqi B; Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
  • Zakimi N; Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
  • Joseph T; Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
  • Birrueta JO; Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
  • Chen WC; Department of Neurosurgery, Johns Hopkins University, Baltimore, MD, USA.
  • Bush NAO; Department of Neurological Surgery, Northwestern University, Chicago, IL, USA.
  • Hervey-Jumper SL; Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
  • Klein OD; Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
  • Toedebusch CM; Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA, USA.
  • Horbinski CM; Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.
  • Magill ST; Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
  • Bhaduri A; Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
  • Perry A; Department of Pediatrics, University of California San Francisco, San Francisco, CA,USA.
  • Dickinson PJ; Department of Pediatrics, University of California San Francisco, San Francisco, CA,USA.
  • Heimberger AB; Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.
  • Ashworth A; Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
  • Crouch EE; Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
  • Raleigh DR; Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
bioRxiv ; 2023 Jul 11.
Article em En | MEDLINE | ID: mdl-37503127
ABSTRACT
Meningiomas are the most common primary intracranial tumors1-3. Treatments for patients with meningiomas are limited to surgery and radiotherapy, and systemic therapies remain ineffective or experimental4,5. 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 NOTCH37,8 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2023 Tipo de documento: Article
Texto completo
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Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2023 Tipo de documento: Article