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Neuropilin-2-expressing breast cancer cells mitigate radiation-induced oxidative stress through nitric oxide
Ayush Kumar1, Hira Lal Goel1, Christi A Wisniewski1
1Department of Molecular, Cell and Cancer Biology.
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 subpopulations 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-associated protein 1 (KEAP1) and, consequently, nuclear factor erythroid 2-related factor 2-mediated (NFE2L2-mediated) transcription of antioxidant response genes. Inhibiting VEGF binding to NRP2, using a humanized 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 with 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.
Insights
Targeting neuropilin-2 (NRP2) enhances triple-negative breast cancer (TNBC) sensitivity to radiation. Inhibiting NRP2 disrupts cancer cell antioxidant defenses, leading to tumor regression and improved radiotherapy outcomes in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy Research
Background:
- Triple-negative breast cancer (TNBC) exhibits high recurrence rates post-radiotherapy, necessitating novel therapeutic strategies.
- Neuropilin-2 (NRP2), a receptor for vascular endothelial growth factor (VEGF), is found on TNBC stem-like cells and implicated in radioresistance.
Purpose of the Study:
- To investigate NRP2 as a therapeutic target for enhancing TNBC radiosensitivity.
- To elucidate the molecular mechanism by which NRP2 signaling contributes to radioresistance in TNBC.
Main Methods:
- Utilized a humanized monoclonal antibody (mAb) to inhibit VEGF binding to NRP2.
- Assessed the impact of NRP2 inhibition on nitric oxide (NO) production, antioxidant gene transcription (NFE2L2 pathway), and radiosensitivity in TNBC cell lines, organoids, and patient-derived xenografts.
Main Results:
- VEGF/NRP2 signaling promotes NO production via NOS2 and Gli1, which activates the NFE2L2 antioxidant response pathway.
- Inhibition of VEGF/NRP2 signaling leads to NFE2L2 degradation, increasing vulnerability to irradiation.
- Combined treatment with NRP2 mAb and radiation significantly reduced tumor necrosis and regression in patient-derived xenografts.
Conclusions:
- NRP2 is a critical mediator of radioresistance in TNBC by regulating antioxidant responses.
- Targeting NRP2 with a mAb represents a promising strategy to sensitize TNBC to radiotherapy, offering a new therapeutic avenue.
