血管内皮细胞源性的外泌体通过Notch信号通路增强肿瘤细胞可塑性的机制研究

骨肉瘤是最常见的原发性恶性骨肿瘤，血管新生旺盛，预后差。目前，血管靶向药物对骨肉瘤患者的治疗效果并不理想，关于骨肉瘤与血管微环境互作的机制研究也未有突破性进展。前期研究发现，骨肉瘤细胞与血管内皮细胞存在相互招募的现象，肿瘤细胞可与脉管系统相连，形成血管网络样结构。此外，血管周围的骨肉瘤细胞表达周皮细胞标志分子，血管内皮细胞还可以通过外泌体引起骨肉瘤细胞内Notch信号通路和黏附分子的上调。我们提出科学假说：血管内皮细胞源性外泌体可以激活骨肉瘤细胞内的Notch信号通路，使其获得更强的干性和可塑性，形成周皮拟态，继而影响肿瘤的恶性进展。因此，本项目拟通过细胞模型、斑马鱼模型和小鼠模型分析血管内皮细胞源性外泌体对骨肉瘤可塑性以及周皮拟态形成的影响，阐明外泌体通过Notch信号通路调控该过程的分子机理。研究成果将有助于理解血管微环境对骨肉瘤发生发展的影响，并为靶向治疗提供理论借鉴和有效策略。

Osteosarcoma (OS) is the most common malignant primary bone tumor, characterized with angiogenesis and poor prognosis. Yet, drug therapy targeting vascular endothelial cells (VECs) could not achieve efficient outcome. Our previous studies found that osteosarcoma cells (OSCs) and VECs could be recruited by each other. OSCs could closely adhere to VECs and help form vascular network, expressing pericyte markers. VECs might secreted exosomes that upregulating adhesion factor and Notch signaling pathway of OSCs. We thus propose a hypothesis that OSCs recruited around blood vessels present stronger ability of stemness and cell plasticity, accompanied with the activation of Notch signaling pathway. Besides, VECs could induce OSCs to mimic pericyte characteristics and then promote tumor progression. In this project, we aim to analyze the role of exosomes derived from VECs on influencing cell plasticity and pericyte mimicry of OSCs via cell, zebrafish and mouse model and elucidate the molecular mechanism of Notch signaling pathway on regulating this process. This study would help better understand the contribution of vascular microenvironment on the progression of OS, which might provide theoretical reference and effective strategy for target therapeutics of OS.