Abstract：
Osteosarcoma (OS) is a highly malignant bone tumour that has seen little improvement in treatment modalities in the past 30 years. Understanding what molecules contribute to OS biology could aid in the discovery of novel therapies. Extracellular vesicles (EVs) serve as a mode of cell-to-cell communication and have the potential to uncover novel protein signatures. In our research, we developed a novel pipeline to isolate, characterize, and profile EVs from normal bone and osteosarcoma tissue explants from canine OS patients. Proteomic analysis of vesicle preparations revealed a protein signature related to protein metabolism. One molecule of interest, PSMD14/Rpn11, was explored further given its prognostic potential in human and canine OS, and its targetability with the drug capzimin. In vitro experiments demonstrated that capzimin induces apoptosis and reduces clonogenic survival, proliferation, and migration in two metastatic canine OS cell lines. Capzimin also reduces the viability of metastatic human OS cells cultured under 3D conditions that mimic the growth of OS cells at secondary sites. This unique pipeline can improve our understanding of OS biology and identify new prognostic markers and molecular targets for both canine and human OS patients.
摘要：
骨肉瘤（OS）是一种高度恶性的骨肿瘤，在过去的30年中，治疗方式几乎没有改善。了解哪些分子有助于OS生物学可以帮助发现新疗法。细胞外囊泡（EV）充当细胞间通讯的一种模式，并有可能发现新的蛋白质特征。在我们的研究中,我们开发了一种新的管道来隔离，表征，并对来自犬OS患者的正常骨和骨肉瘤组织外植体的EV进行分析。囊泡制剂的蛋白质组学分析揭示了与蛋白质代谢相关的蛋白质特征。一个感兴趣的分子，PSMD14/Rpn11，进一步探讨了其在人和犬OS中的预后潜力，以及它与药物卡齐明的靶向性。体外实验表明，卡齐明诱导细胞凋亡并降低克隆存活，扩散,和两种转移性犬OS细胞系的迁移。Capzimin还降低了在模拟OS细胞在次要部位生长的3D条件下培养的转移性人OS细胞的活力。这种独特的管道可以提高我们对OS生物学的理解，并为犬和人类OS患者确定新的预后标志物和分子靶标。
