TEP RNA 通过整合素αIIbβ3促进多发性骨髓瘤发展的机制研究

Multiple myeloma (MM) is a malignant tumor of the plasma cell. MM already becomes the second most common hematological neoplasm. Studies have shown that angiogenesis is one of the important mechanisms of the pathogenesis and progression of MM, which is closely related to the microenvironment of bone marrow. There are few studies on the platelets in MM microenvironment. Recent studies show that tumor TEP (Tumor-Educated-Platelet, TEP) can carry RNA of tumor origin and accurately diagnose primary tumors in solid tumor microenvironment. But it is not clear whether the blood cancer MM TEP has the same effect. The pre-experimen results showed that there was a difference between the MM and the normal human platelet RNA, suggesting the possibility of MM TEP. Based on the pre-experiment and previous research, we continue to collect the confirmed MM cases, and verify the TEP RNA by the second-generation RNA sequencing. Through the co culture of MM TEP and MM cell lines in vitro, we intend to observe self activation of the MM TEP and the structure and expression changes of the cell surface main adhesion integrin αIIbβ3. The effects of TEP RNA on angiogenesis and invasive function of MM will be further investigated and verified in primary MM cells in vitro and MM tumor bearing mice model in vivo. This study intend to reveal the new function of platelets , and provides new ideas and strategies for the target treatment of MM cells and bone marrow microenvironment.

多发性骨髓瘤(MM) 是骨髓浆细胞恶性肿瘤，发病率居血液肿瘤第二位。血管新生是MM发病及进展的重要机制之一，与骨髓微环境密切相关。对于MM微环境中广泛存在的血小板，研究甚少。最新研究表明，实体肿瘤微环境中肿瘤血小板（TEP）能携带肿瘤来源的RNA，并能精准诊断原发肿瘤。但血液系统来源的MM TEP是否具有同样的作用尚不清楚。预实验结果显示MM患者与正常人血小板 RNA存在差异。本课题拟在预实验和前期研究基础上，继续收集确诊MM病例进行RNA二代测序验证，通过体外MM TEP与MM细胞株共培养，观察MM TEP自身活化和细胞表面主要粘附物整合素αIIbβ3的结构和表达变化，进一步探讨TEP RNA对MM血管新生和侵袭功能的影响，并在体外原代MM 细胞和体内MM荷瘤小鼠模型上进行验证。本研究为揭示血小板新功能，将血小板作为潜在的治疗靶点，同时靶向治疗MM细胞和骨髓微环境提供新的思路和策略。

多发性骨髓瘤(MM) 是骨髓浆细胞恶性克隆性增殖肿瘤，发病率居血液肿瘤第二位，至今仍不能治愈。MM的发生与骨髓微环境密切相关。对于微环境中广泛存在的血小板，研究甚少。最新研究表明，实体肿瘤微环境中肿瘤教化血小板（TEP）能携带肿瘤来源的RNA，并能精准诊断原发肿瘤。但血液系统来源的MM TEP是否具有同样的作用尚不清楚。本项目在预实验和前期研究基础上，继续收集确诊MM病例外周血进行RNA二代测序，结果发现MM患者存在特异的TEP RNA，且MM患者外周血易见活化血小板。进一步扫描电镜和透射电镜发现MM患者血小板超微结构和内部线粒体均存在明显差异。MM患者TEG功能和血小板聚集功能、外周血中miRNA 和PiRNA与正常人相比均存在明显差异。通过体外MM TEP与MM细胞共培养，发现MM TEP更易被激活活化。MM患者中bFGF，IGF-1、IL-6、TGF-β1、MMP2、MMP9浓度升高，PF4浓度降低，差异均具有统计学意义，证明TEP RNA能促进MM细胞侵袭功能。此外，本研究还发现共培养MM细胞与血小板之间可存在特殊的隧道纳米管结构（TNTs），为后续探讨TEP形成和转归机制奠定了基础。本研究为揭示血小板新功能，将血小板作为潜在的治疗靶点，同时靶向治疗MM细胞和骨髓微环境提供了新的思路和策略。