m6A methylation reader IGF2BP2 activates endothelial cells to promote angiogenesis and metastasis of lung adenocarcinoma

Molecular Cancer

Research

Dengfeng Yang¹  Yilan Yu²  Kejian Wang²  Yufeng Lv³  Aina Liu⁴  Ping Sun⁴  Huijuan Zhang⁴  Shizhuang Wei⁵  Congxian Lu⁵  Xicheng Song⁵  Ruxian Tian⁵  Han Fang⁵  Qi Sun⁵  Ying Guo⁵  Hua Zhang⁵  Yakui Mou⁶  Guohua Yu⁷  Xiaofeng Yu⁸  Yingjian Song⁸  Chengyu Huang⁹  Qiong Song⁹  Chuanliang Jia⁹  Ting Li^1,10  Yixuan Chen^1,10  Ke Mo^1,11  Kaiyu Song^1,12  Jin Zhou^1,12 

[1] Biology Institute, Guangxi Academy of Sciences, 530007, Nanning, Guangxi, China;Biology Institute, Guangxi Academy of Sciences, 530007, Nanning, Guangxi, China;Experimental Center of BIOQGene, YuanDong International Academy Of Life Sciences, 999077, Hong Kong, China;Department Of Basic Science, YuanDong Life California Ivy Research Institute, 90069, West Hollywood, CA, USA;Department of Oncology, Yantai Yuhuangding Hospital of Qingdao University, 264000, Yantai, Shandong, China;Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital of Qingdao University, 264000, Yantai, Shandong, China;Key Laboratory of Spatiotemporal Single-Cell Technologies and Translational Medicine, 264000, Yantai, Shandong, China;Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital of Qingdao University, 264000, Yantai, Shandong, China;Key Laboratory of Spatiotemporal Single-Cell Technologies and Translational Medicine, 264000, Yantai, Shandong, China;Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, 264000, Yantai, Shandong, China;Department of Pathology, Yantai Yuhuangding Hospital of Qingdao University, 264000, Yantai, Shandong, China;Department of Thoracic Surgery, Yantai Yuhuangding Hospital of Qingdao University, 264000, Yantai, Shandong, China;Key Laboratory of Spatiotemporal Single-Cell Technologies and Translational Medicine, 264000, Yantai, Shandong, China;Key Laboratory of Spatiotemporal Single-Cell Technologies and Translational Medicine, 264000, Yantai, Shandong, China;Department Of Basic Science, YuanDong Life California Ivy Research Institute, 90069, West Hollywood, CA, USA;Key Laboratory of Spatiotemporal Single-Cell Technologies and Translational Medicine, 264000, Yantai, Shandong, China;Department Of Basic Science, YuanDong Life California Ivy Research Institute, 90069, West Hollywood, CA, USA;Experimental Center of BIOQGene, YuanDong International Academy Of Life Sciences, 999077, Hong Kong, China;Key Laboratory of Spatiotemporal Single-Cell Technologies and Translational Medicine, 264000, Yantai, Shandong, China;Department of Endocrinology, Yantai Yuhuangding Hospital of Qingdao University, 264000, Yantai, Shandong, China;

关键词: Lung adenocarcinoma;    Single-cell RNA sequencing;    Metastasis;    N-methyladenosine;    Angiogenesis;    IGF2BP2;    Exosomes;   

DOI  :  10.1186/s12943-023-01791-1

 received in 2023-01-15, accepted in 2023-05-16,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundLung adenocarcinoma (LUAD) is a common type of lung cancer with a high risk of metastasis, but the exact molecular mechanisms of metastasis are not yet understood.MethodsThis study acquired single-cell transcriptomics profiling of 11 distal normal lung tissues, 11 primary LUAD tissues, and 4 metastatic LUAD tissues from the GSE131907 dataset. The lung multicellular ecosystems were characterized at a single-cell resolution, and the potential mechanisms underlying angiogenesis and metastasis of LUAD were explored.ResultsWe constructed a global single-cell landscape of 93,610 cells from primary and metastatic LUAD and found that IGF2BP2 was specifically expressed both in a LUAD cell subpopulation (termed as LUAD_IGF2BP2), and an endothelial cell subpopulation (termed as En_IGF2BP2). The LUAD_IGF2BP2 subpopulation progressively formed and dominated the ecology of metastatic LUAD during metastatic evolution. IGF2BP2 was preferentially secreted by exosomes in the LUAD_IGF2BP2 subpopulation, which was absorbed by the En_IGF2BP2 subpopulation in the tumor microenvironment. Subsequently, IGF2BP2 improved the RNA stability of FLT4 through m6A modification, thereby activating the PI3K-Akt signaling pathway, and eventually promoting angiogenesis and metastasis. Analysis of clinical data showed that IGF2BP2 was linked with poor overall survival and relapse-free survival for LUAD patients.ConclusionsOverall, these findings provide a novel insight into the multicellular ecosystems of primary and metastatic LUAD, and demonstrate that a specific LUAD_IGF2BP2 subpopulation is a key orchestrator promoting angiogenesis and metastasis, with implications for the gene regulatory mechanisms of LUAD metastatic evolution, representing themselves as potential antiangiogenic targets.

【 授权许可】

CC BY   
© The Author(s) 2023

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