血管周围NOTCH3+干细胞驱动脑膜瘤肿瘤发生并对放疗产生抗药性。

IF 29.7 1区 医学 Q1 ONCOLOGY Cancer discovery Pub Date : 2024-10-04 DOI:10.1158/2159-8290.CD-23-1459
Abrar Choudhury, Martha A Cady, Calixto-Hope G Lucas, Hinda Najem, Joanna J Phillips, Brisa Palikuqi, Naomi Zakimi, Tara Joseph, Janeth O Birrueta, William C Chen, Nancy A 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
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引用次数: 0

摘要

脑膜瘤是最常见的原发性颅内肿瘤。对脑膜瘤患者的治疗仅限于手术和放射治疗,全身治疗仍然无效或处于试验阶段。高分化脑膜瘤普遍存在放疗耐药性,而驱动脑膜瘤肿瘤发生和放疗耐药性的细胞类型和信号机制尚不完全清楚。在这里,我们报告了NOTCH3驱动脑膜瘤肿瘤发生和对放疗的耐受性,并发现血管周围NOTCH3+干细胞在人类、狗和小鼠的脑膜瘤中是保守的。在基因工程小鼠模型和异种移植物中,我们将单细胞转录组学与系谱追踪和成像方法相结合,结果表明NOTCH3驱动肿瘤的始发能力、细胞增殖、血管生成和对放疗的耐受性,从而增加脑膜瘤的生长并降低存活率。为了将这些发现应用到患者身上,我们证明了稳定 NOTCH3 细胞外负调控区的抗体可以阻止脑膜瘤的肿瘤发生,并使脑膜瘤对放疗敏感,从而减少肿瘤生长,提高生存率。
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Perivascular NOTCH3+ Stem Cells Drive Meningioma Tumorigenesis and Resistance to Radiotherapy.

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 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. Significance: There are no effective systemic therapies to treat meningiomas, and meningioma stem cells are poorly understood. Here, we report perivascular NOTCH3+ stem cells to drive meningioma tumorigenesis and resistance to radiotherapy. Our results identify a conserved mechanism and a therapeutic vulnerability to treat meningiomas that are resistant to standard interventions.

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来源期刊
Cancer discovery
Cancer discovery ONCOLOGY-
CiteScore
22.90
自引率
1.40%
发文量
838
审稿时长
6-12 weeks
期刊介绍: Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.
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