FcγRIIB受体调控肿瘤转移的作用及机制研究

Tumor metastasis is responsible for as much as 90% of cancer-associated mortality worldwide. However, Its process and molecular mechanism are poorly understood and it's of great importance to clarify them. Our previous work showed that metastasis of melanoma was much more severer in FcγRIIB-/- mice compared to wild type mice, yet the mechanism remains elusive. This project will focus on the following contents: ⑴ The concrete mechanism of FcγRIIB in regulating metastasis-initiating cells (MIC) formation. It will focus on the fusion process of tumor cells and hematopoietic stem cell(HSC) and the functional changes of the fusion hybrids which may acquire stemness after epigenetic regulation, such as reprogramming ,which finally formed MIC. ⑵ The roles of FcγRIIB in the progress of metastasis. FcγRIIB deficiency will result in inflammatory microenvironment, which affects the stemness of circulation tumor cell and formation of pre-metastasis niche. The mechanism of the process will be investigated. ⑶ Using activating FcγR receptor knock-out mice (FcRγ-/-) and clinical samples, we will clarify the regulatory role of FcγRIIB in the important processes during tumor metastasis on molecular ,cellular and animal levels, which will provide theoretical and experimental basis for research and development of new drugs preventing and treating tumor metastasis.

全世界癌症患者死亡约90%可归咎于肿瘤转移，阐明其发生过程及具体机制是目前亟待解决的重大科学问题。本课题组前期研究发现FcγRIIB-/-小鼠较WT小鼠更易发生黑色素瘤转移，具体机制未明。本项目主要研究内容包括：⑴FcγRIIB调控肿瘤转移起始细胞（MIC）形成的具体机制，重点研究其调控肿瘤细胞与骨髓造血干细胞HSC融合，以及融合细胞表观遗传修饰、重编程及干性（stemness）获得相关环节的分子机制。⑵FcγRIIB对循环肿瘤细胞及转移灶的调控机制，以FcγRIIB缺失所导致炎症微环境为出发点，研究肿瘤转移进展过程中循环肿瘤细胞干性调节及转移前Niche的形成机制。（3）应用激活型受体FcRγ-/-小鼠及临床样本验证上述研究结论，从分子、细胞、动物模型和临床病例等多个水平，阐明FcγRIIB在肿瘤转移发生发展各重要环节的确切调控机制，为研发预防和治疗肿瘤转移的新药提供理论依据和实验基础。

恶性肿瘤是当今严重威胁人类健康的疾病之一，全世界癌症患者的死亡约90%可归咎于肿瘤转移。肿瘤转移过程中涉及众多影响因素，调控机制极其复杂且尚不清楚。通过FcγR受体相关模式小鼠，我们揭示了FcγRIIB对于肿瘤转移无显著调控作用，而Fcer1g在肿瘤转移中起着关键作用。通过皮下移植瘤模型、流式细胞术以及模型中循环免疫复合物（CIC）含量的测定，发现上述肿瘤转移结果与ADCC作用无关而是与血小板及中性粒细胞交互作用的结果。从机制上讲，Fcer1g功能下调的血小板更易与循环肿瘤细胞结合，导致趋化因子CXCL5和CXCL7分泌增加而招募大量中性粒细胞到达早期转移Niche，并促进循环肿瘤细胞HIF-1α表达，进一步通过增强其转移特性或促进CTMs 形成，综合促进肿瘤转移。因此，这些结果表明或许可从免疫细胞与循环肿瘤细胞交互作用的角度寻找干预肿瘤转移的靶点。