NR3B2主导胶质瘤细胞与TAMs融合的作用机制及临床意义

肿瘤相关巨噬细胞（TAMs）与瘤细胞互作维持胶质瘤高侵袭恶性表型，但高侵袭瘤细胞的来源及恶性表型调控机制尚不清楚。我们前期发现，NR3B2与胶质瘤侵袭相关，胶质瘤细胞NR3B2与Nanog互作激活STAT 3调控 GM-CSF，NR3B2触发肿瘤细胞代谢机制生成Lactate，对活化、招募M2型TAMs发挥关键作用；胶质瘤存在瘤细胞与TAMs融合，我们亦发现NR3B2high/CD163high融合细胞亚群。本项目提出“NR3B2high胶质瘤细胞促进M2型TAMs，NR3B2high瘤细胞与CD163high TAMs融合，产生更强侵袭力的肿瘤干细胞（CSCs）”的假说。本项目拟采用体外融合、免疫印迹、RNAi等技术阐明胶质瘤NR3B2激活STAT3及PKM2/Lactate途径的机制，胶质瘤细胞与TAMs 融合的生物学特性与机制，为靶向异质性肿瘤细胞与微环境的治疗策略提供新思路和靶点。

Interactions between tumor-associated macrophages (TAMs) and tumor cells maintain highly invasive phenotype of glioma cells, but the source of highly invasive tumor cells and regulation mechanism of malignant phenotype is unclear. We previously found that NR3B2 expression correlated with the invasion of human glioma, NR3B2 interacted with Nanog and activated STAT3 to regulate GM-CSF, NR3B2 triggered metabolism of tumor cells to produce Lactate, subsequently played a key role in the activation and recuitment of M2 TAMs. Based on the existence of spontaneous fusion between tumor cells and TAMs in glioma, we also found NR3B2high/CD163high fusion cell subsets. The project proposed the hypothesis that NR3B2high glioma cells promote polarization of M2 TAMs, NR3B2high tumor cells fused with CD163high TAMs and subsequently produce cancer stem cells (CSCs) with stronger invasiveness. Multiple molecular techniques including in vitro fusion, western blotting, RNAi technology will be applied to decipher the mechanism that NR3B2 activates STAT3 and PKM2/Lactate pathway, and clarify the biological characteristics and mechanisms of fusion between glioma cells and TAMs. This study will provide new ideas and targets for the therapy strategies targeting tumor cells with heterogeneity and tumor microenvironment in glioma.