Loading...
Thumbnail Image
Publication

Neuropilin-2 expressing cells in breast cancer are S-nitrosylation hubs that mitigate radiation-induced oxidative stress

Kumar, Ayush
Goel, Hira
Wisniewski, Christi
Wang, Tao
Geng, Yansong
Wang, Mengdie
Goel, Shivam
Hu, Kai
Li, Rui
Zhu, Lihua Julie
... show 5 more
Embargo Expiration Date
Abstract

The high rate of recurrence after radiation therapy in triple-negative breast cancer (TNBC) indicates that novel approaches and targets are needed to enhance radiosensitivity. Here, we report that neuropilin-2 (NRP2), a receptor for vascular endothelial growth factor (VEGF) that is enriched on sub-populations of TNBC cells with stem cell properties, is an effective therapeutic target for sensitizing TNBC to radiotherapy. Specifically, VEGF/NRP2 signaling induces nitric oxide synthase 2 (NOS2) transcription by a mechanism dependent on Gli1. NRP2-expressing tumor cells serve as a hub to produce nitric oxide (NO), an autocrine and paracrine signaling metabolite, which promotes cysteine-nitrosylation of Kelch-like ECH-asssociated protein 1 (KEAP1) and, consequently, nuclear factor erythroid 2-related factor 2 (NFE2L2)-mediated transcription of antioxidant response genes. Inhibiting VEGF binding to NRP2, using a humanized monoclonal antibody (mAb), results in NFE2L2 degradation via KEAP1 rendering cell lines and organoids vulnerable to irradiation. Importantly, treatment of patient-derived xenografts with the NRP2 mAb and radiation resulted in significant tumor necrosis and regression compared to radiation alone. Together, these findings reveal a targetable mechanism of radioresistance and they support the use of NRP2 mAb as an effective radiosensitizer in TNBC.

Source

Kumar A, Goel H, Wisniewski C, Wang T, Geng Y, Wang M, Goel S, Hu K, Li R, Zhu LJ, Clark JL, Ferreira LM, Brehm M, Fitzgerald TJ, Mercurio AM. Neuropilin-2 expressing cells in breast cancer are S-nitrosylation hubs that mitigate radiation-induced oxidative stress. J Clin Invest. 2024 Oct 1:e181368. doi: 10.1172/JCI181368. Epub ahead of print. PMID: 39352757.

Year of Medical School at Time of Visit
Sponsors
Dates of Travel
DOI
10.1172/JCI181368
PubMed ID
39352757
Other Identifiers
Notes
Funding and Acknowledgements
Corresponding Author
Related Resources
Related Resources
Repository Citation
Rights
Copyright © 2024, Kumar et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Attribution 4.0 International