A 3D In Vitro Co-Culture Model to Investigate Tumor-Endothelial Interactions in NF2-Associated Meningiomas

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ID: 325609
2026
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Abstract
Abstract Background NF2-associated meningiomas and schwannomas are vascular tumors, and while VEGF inhibition with bevacizumab has benefited some NF2-related schwannomas, most NF2-associated meningiomas remain nonresponsive. Methods Leveraging our transcriptomic data, we performed Gene Ontology (GO) analysis comparing NF2-deficient meningioma cells with NF2-expressing arachnoid cells (ACs). We then established a 3D in vitro angiogenesis model by co-culturing NF2-null meningioma cells with human umbilical vein endothelial cells (HUVECs). Endothelial sprouting was assessed by CD31/PECAM immunostaining. Effects of third-generation mTORC1-selective inhibitor RMC-6272 as well as APLN knock-out using CRISPR-Cas9 gene editing were also examined. Results GO analysis identified vascular development among the top significantly upregulated pathways in NF2-deficient cells. In 3D co-culture, ECs formed radially sprouting tube-like networks from the spheroid surface, and our data support an angiogenesis phenotype driven by meningioma cells. Given these results along with hyperactivation of mTORC1 upon NF2-deficiency, we examined whether RMC-6272 disrupts meningioma-driven angiogenesis. RMC-6272 potently suppressed EC sprouting. Cross-referencing baseline transcriptomic data we identified Apelin (APLN), the ligand for APLNR, as a basally upregulated angiogenic factor in NF2-deficient meningiomas. qRT-PCR confirmed increased APLN expression in NF2-null immortalized and patient-derived meningioma lines, with reduced expression upon mTORC1 inhibition. Apelin-13 stimulation enhanced sprouting, whereas APLN deletion reduced endothelial sprouting. Conclusions Here we establish a 3D-tumoroid model and implicate tumor-derived Apelin as an important contributor to NF2-associated meningioma angiogenesis. Our data also suggest that APLN expression is regulated, at least in part, by mTORC1. T1ogether, these results provide a preclinical platform for investigating angiogenic vulnerabilities beyond VEGF in NF2-deficient meningiomas.
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Authors Srirupa Bhattacharyya, Roberta L. Beauchamp, Vijaya Ramesh
Journal Neuro-Oncology Advances
Year 2026
DOI
10.1093/noajnl/vdag218
URL
https://doi.org/10.1093/noajnl/vdag218
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