m 6 A methylation reader IGF2BP2 activates endothelial cells to promote angiogenesis and metastasis of lung adenocarcinoma

• Published in: Molecular cancer 2023-06, Vol.22 (1), p.99
• Main Authors: Fang, Han, Sun, Qi, Zhou, Jin, Zhang, Huijuan, Song, Qiong, Zhang, Hua, Yu, Guohua, Guo, Ying, Huang, Chengyu, Mou, Yakui, Jia, Chuanliang, Song, Yingjian, Liu, Aina, Song, Kaiyu, Lu, Congxian, Tian, Ruxian, Wei, Shizhuang, Yang, Dengfeng, Chen, Yixuan, Li, Ting, Wang, Kejian, Yu, Yilan, Lv, Yufeng, Mo, Ke, Sun, Ping, Yu, Xiaofeng, Song, Xicheng
• Format: Article
• Language: English
• Subjects: Adenocarcinoma of Lung - genetics; Ecosystem; Endothelial Cells; Humans; Lung Neoplasms - genetics; Methylation; Neoplasm Recurrence, Local; Phosphatidylinositol 3-Kinases; RNA-Binding Proteins - genetics; Tumor Microenvironment
• ISSN: 1476-4598

Lung 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. This 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. We 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 m A 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. Overall, 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.