TY - JOUR
T1 - Perivascular NOTCH3+ Stem Cells Drive Meningioma Tumorigenesis and Resistance to Radiotherapy
AU - Choudhury, Abrar
AU - Cady, Martha A.
AU - Lucas, Calixto Hope G.
AU - Najem, Hinda
AU - Phillips, Joanna J.
AU - Palikuqi, Brisa
AU - Zakimi, Naomi
AU - Joseph, Tara
AU - Birrueta, Janeth O.
AU - Chen, William C.
AU - Bush, Nancy A.Oberheim
AU - Hervey-Jumper, Shawn L.
AU - Klein, Ophir D.
AU - Toedebusch, Christine M.
AU - Horbinski, Craig M.
AU - Magill, Stephen T.
AU - Bhaduri, Aparna
AU - Perry, Arie
AU - Dickinson, Peter J.
AU - Heimberger, Amy B.
AU - Ashworth, Alan
AU - Crouch, Elizabeth E.
AU - Raleigh, David R.
N1 - Publisher Copyright:
© 2024 American Association for Cancer Research.
PY - 2024/10
Y1 - 2024/10
N2 - 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 that NOTCH3 drives meningi-oma 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.
AB - 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 that NOTCH3 drives meningi-oma 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.
UR - https://www.scopus.com/pages/publications/85205741014
UR - https://www.scopus.com/pages/publications/85205741014#tab=citedBy
U2 - 10.1158/2159-8290.CD-23-1459
DO - 10.1158/2159-8290.CD-23-1459
M3 - Article
C2 - 38742767
AN - SCOPUS:85205741014
SN - 2159-8274
VL - 14
SP - 1823
EP - 1837
JO - Cancer discovery
JF - Cancer discovery
IS - 10
ER -