Nicotinamide N-methyltransferase negatively regulates metastasis-promoting property of cancer-associated fibroblasts in lung adenocarcinoma  

作　　者：Peiyu Wang Guangxi Wang Haoran Li Yuyao Yuan Haiming Chen Shaodong Wang Zewen Sun Fanjie Meng Yun Li Fan Yang Jun Wang Kezhong Chen Mantang Qiu 

机构地区：[1]Department of Thoracic Surgery,Peking University People’s Hospital,Beijing,P.R.China [2]Thoracic Oncology Institute,Peking University People’s Hospital,Beijing,P.R.China [3]Research Unit of Intelligence Diagnosis and Treatment in Early Non-small Cell Lung Cancer,Chinese Academy of Medical Sciences,2021RU002,Peking University People’s Hospital,Beijing,P.R.China [4]Department of Thoracic Surgery,The First Affiliated Hospital of Zhengzhou University,Zhengzhou,Henan,P.R.China [5]Department of Pathology,School of Basic Medical Sciences,Institute of Systems Biomedicine,Peking-Tsinghua Center for Life Sciences,Peking University Health Science Center,Beijing,P.R.China [6]Department of Thoracic Surgery,Beijing Institute of Respiratory Medicine and Beijing Chao Yang Hospital,Capital Medical University,Beijing,P.R.China

出　　处：《Cancer Communications》2025年第2期110-137,共28页癌症通讯(英文)

基　　金：National Natural Science Foundation of China,Grant/Award Numbers:92059203,82173386;National Key R&D Program of China,Grant/Award Number:2023YFF0723500;Research Unit of Intelligence Diagnosis and Treatment in Early Non-small Cell Lung Cancer,Chinese Academy of Medical Sciences,Grant/Award Number:2021RU002;Medical and Health Science and Technology Innovation project,Grant/Award Number:2021-I2M-002;Beijing Nova Program,Grant/Award Number:20230484314;Innovation Fund for Excellent PhD student of Peking University Health Science Center,Grant/Award Number:2022-58。

摘　　要：Background:Recurrence and metastasis remain significant challenges in lung adenocarcinoma(LUAD)after radical resection.The mechanisms behind the recurrence and metastasis of LUAD remain elusive,and deregulated cellular metabolism is suspected to play a significant role.This study explores the metabolic and epigenetic regulation mediated by nicotinamide N-methyl transferase(NNMT)in LUAD.Methods:Untargeted metabolomic analyses were performed to detect metabolism irregularities.Single-cell RNA sequencing(RNA-seq)databases and multiplex immunofluorescence analysis were used to identify the location of NNMT within the tumor microenvironment.The biological functions of NNMT were investigated both in vitro and in vivo,with RNA-seq and chromatin immunoprecipitation-PCR providing insights into underlying mechanisms.Finally,single-cell RNA-seq data and immunohistochemistry of primary tumors were analyzed to validate the main findings.Results:Untargeted metabolomic analyses revealed metabolic aberrations in amino acids,organic acids,lipids,and nicotinamide pathways,which are linked to metastasis of non-small cell lung cancer.NNMT is a key enzyme in nicotinamide metabolism,and we found the bulk tissue mRNA level of NNMT gene was inversely associated with LUAD metastasis.NNMT was proved to be predominantly expressed in cancer-associated fibroblasts(CAFs)within the stromal regions of LUAD,and a low stromal NNMT expression was identified as a predictor of poor disease-free survival following radical resection of LUAD.The isolation and primary culture of CAFs from LUAD enabled in vitro and in vivo experiments,which confirmed that NNMT negatively regulated the metastasispromoting properties of CAFs in LUAD.Mechanistically,the downregulation of NNMT led to an increase in intracellular methyl groups by reducing the activity of the methionine cycle,resulting in heightened methylation at H3K4me3.This alteration triggered the upregulation of genes involved in extracellular matrix remodeling in CAFs,including those encoding collagens,i

关 键 词：Nicotinamide N-methyl transferase Lung cancer Cancer-associated fibroblast Extracellular matrix Metastasis 

分 类 号：R73[医药卫生—肿瘤]