LINC01094通过编码短肽调节巨噬细胞吞噬功能介导肺癌肿瘤微环境调控的机制

肿瘤相关巨噬细胞(TAM)是肺癌微环境中重要的组成成分，并与肺癌的发展及转移密切相关，但肺癌TAM促肿瘤的分子机制尚不明确。本项目前期通过单细胞转录组测序，发现LINC01094在肺癌TAM中异常高表达。通过整合蛋白质谱，我们发现其能编码具有生物学活性的短肽。更重要的是在肺癌TAM细胞中敲低LINC01094后，其促肿瘤活性部分转化为抗肿瘤活性，提示LINC01094可能与肺癌TAM的促肿瘤活性有关。基于此，本项目拟针对患者来源TAM细胞、体外诱导及动物模型巨噬细胞开展LINC01094的功能学研究。通过单细胞转录组测序、蛋白质组、IP-LC-MS/MS以及ChIP-qPCR等分子生物学技术深入其上下游调控机制，以明确其在肺癌TAM中发挥的功能。本项目将从LncRNA角度出发为TAM抗肿瘤活性的机制提供依据，并为基于TAM的免疫治疗提供新的靶点。

Tumor-associated macrophage (TAM) is one of the most important infiltrated immune cells in the microenvironment of lung tumors. Emerging evidence demonstrated that the TAM involved in proliferation and metastasis of tumor cells, but the underlying mechanisms remain elusive. In our previous studies, we performed single-cell transcriptome analysis of lung tumors and identified the distinct transcriptome signature of lung cancer. Among these distinct genes, we found that LINC01094 was significantly overexpression in TAMs as compared to other cells in the microenvironment of lung cancer or macrophages isolated from peripheral blood. Further functional studies reveal that knockdown LINC01094 in TAM significantly reduced M2 related cytokines produced by TAM and reduced the proliferation of tumor cells in a co-culture system, suggesting the over-amplified LINC01094 in TAM might be required for the tumorigenesis of lung cancer. Also, our preliminary studies on the proteinomics of TAM cells in lung cancer identified a short peptide encoded by LINC01094, and the IP-LC-MS/MS experiments reveal the peptide directly interact with IRF4 and STAT6 in TAM. Based on these observations, we hypothesized that LINC01094 was overexpressed in TAMs of lung cancer and resulted in the accumulated peptide, while the peptide involved in the transcription regulation programs of IRF4 and STAT6 and resulted in activation of genes associated with the phenotype of tumor-associated macrophages. To address this possibility, we plan to systematically investigate the function of LINC01094 in TAMs and the related mechanisms with multiple approaches, including single cell transcriptomics, proteinomics, immunoprecipitation as well as ChIP experiments. Also, we aim to discover the mechanisms underlying LINC01094 encoded peptide in transcriptional regulation. Together, our study will provide new insight into the roles of LncRNAs in macrophage-related tumor immunology and the function of the lncRNA-encoded short peptide in transcriptional regulation.