VEGF/Neuropilin-2 Signaling and Radioresistance in Triple-Negative Breast Cancer

项目摘要 三阴性乳腺癌（TNBC）是一种侵袭性形式的乳腺癌，标准治疗包括： 新辅助化疗、手术治疗和放射治疗。然而，高复发率和 TNBC的低病理完全反应表明，放射抗性是减少TNBC的关键因素。 目前治疗策略的疗效。探索特定途径的文献有限 负责TNBC中的辐射抗性，但大多数数据支持限制活性氧的作用 (ROS)积累我们的实验室研究了血管内皮生长因子（VEGF）结合 神经纤毛蛋白-2（NRP 2）和启动几种癌症干细胞特性。初步数据显示， 富集NRP 2表达细胞并使用对VEGF/NRP 2特异性的功能阻断抗体， 在TNBC类器官中，与单独的任一种处理相比，照射降低了细胞活力。中央 该建议的假设是VEGF/NRP 2通过改变氧化还原稳态诱导辐射抗性， 可以靶向TNBC中更好的治疗结果。这项建议将寻求调查一个可能的 NRP 2调节NOS 2转录的作用及其对减轻ROS积累的贡献。我也会用 单细胞RNA测序技术，以鉴定具有放射抗性的TNBC亚群， 它们是否利用NRP 2/NOS 2信号传导轴。这项建议的另一个方面是， 使用体内模型用放射治疗NRP 2的功能阻断抗体的有效性。我计划确认 这种方法减少了TNBC中的辐射抗性克隆。这项建议的完成将提高 了解TNBC中的辐射抗性，并确定负责这种表型的新分子途径。

PROJECT SUMMARY Triple Negative Breast Cancer (TNBC) is an aggressive form of breast cancer with standard therapy involving neoadjuvant chemotherapy, surgical management, and radiation therapy. However, the high recurrence rate and low pathological complete response of TNBC suggest that radioresistance is a critical factor in the diminished therapeutic efficiency of the current treatment strategy. There is limited literature exploring the specific pathways responsible for radiation resistance in TNBC, but most data support the role of limiting reactive oxygen species (ROS) accumulation. Our lab has studied the role of Vascular Endothelia Growth Factor (VEGF) binding to Neuropilin-2 (NRP2) and initiating several cancer stem cell properties. Preliminary data indicate that radiation enriches for NRP2 expressing cells and using a function blocking antibody specific to VEGF/NRP2 with irradiation decreases cell viability compared to either treatment alone in a TNBC organoid. The central hypothesis of this proposal is that VEGF/NRP2 induces radioresistance by altering redox homeostasis and can be targeted for better therapeutic outcomes in TNBC. This proposal will seek to investigate a possible role of NRP2 regulating NOS2 transcription and its contribution to mitigating ROS accumulation. I will also use single-cell RNA sequencing technology to identify the subpopulations of TNBC that are radioresistant and whether they utilize the NRP2/NOS2 signaling axis. Another aspect of this proposal is to observe the effectiveness of a function blocking antibody of NRP2 with radiation using an in vivo model. I plan to identify if this approach reduces the radioresistant clones in TNBC. The completion of this proposal will heighten the understanding of radioresistance in TNBC and identify a novel molecular pathway responsible for this phenotype.