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Counteracting lineage-specific transcription factor network finely tunes lung adeno-to-squamous transdifferentiation through remodeling tumor immune microenvironment

查看全文 作　　者：Shijie [1]Tang;Yun [1,2]Xue;Zhen [1]Qin;Zhaoyuan [1,13,14]Fang;Yihua [3,4]Sun;Chongzhe [3,4]Yuan;Yunjian [3,4]Pan;Yue [3,4]Zhao;Xinyuan [1]Tong;Jian [1]Zhang;Hsinyi [1]Huang;Yuting [1,6]Chen;Liang [1]Hu;Dasong [5]Huang;Ruiqi [5]Wang;Weiguo [1]Zou;Yuan [3,4]Li;Roman [7,8]KThomas;Andrea [9]Ventura;Kwok-Kin [10]Wong;Haiquan [3,4]Chen;Luonan [1,6,11]Chen;Hongbin [1,6,12]Ji 高影响力作者 机构地区：[1]State Key Laboratory of Cell Biology,Shanghai Institute of Biochemistry and Cell Biology,Center for Excellence in Molecular Cell Science,Chinese Academy of Sciences,Shanghai 200031,China;[2]College of Life Sciences,University of Chinese Academy of Sciences,Beijing 100049,China;[3]Department of Thoracic Surgery,Fudan University Shanghai Cancer Center,Shanghai 200032,China;[4]Department of Oncology,Shanghai Medical College,Fudan University,Shanghai 200032,China;[5]Department of Mathematics,Shanghai University,Shanghai 200444,China;[6]School of Life Science and Technology,Shanghai Tech University,Shanghai 200120,China;[7]Department of Translational Genomics,Center of Integrated Oncology Cologne-Bonn,Medical Faculty,University of Cologne,Cologne 50931,Germany;[8]Department of Pathology,University Hospital Cologne,Cologne 50937,Germany;[9]Cancer Biology and Genetics Program,Memorial Sloan Kettering Cancer Center,New York,NY 10065,USA;[10]Laura and Isaac Perlmutter Cancer Center,New York University Langone Medical Center,New York,NY 10016,USA;[11]Key Laboratory of Systems Biology,Shanghai Institutes for Biological Sciences,Chinese Academy of Sciences,Shanghai 200031,China;[12]School of Life Science,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Chinese Academy of Sciences,Hangzhou 310024,China;[13]Zhejiang University-University of Edinburgh Institute,Zhejiang University School of Medicine,Haining 314400,China;[14]The Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310000,China高影响力机构 出　　处：《National Science Review》索引2023年第10卷第4期,共19页高影响力期刊 基　　金：the National Basic Research Program of China(2017YFA0505500 to H.J.and L.C.,2022YFA1103900to H.J.,2020YFA0803300 to H.J.,2022YFA1004800 to L.C.);the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB19020201 to H.J.,XDB38040400 to L.C.);the National Natural Science Foundation of China(82030083,31621003,32293192,81872312 and 82011540007 to H.J.,31930022 and 12131020 to L.C.,82273093 to Z.F.,82173340and 81871875 to L.H.,82173340 to L.H.,81802279 to H.H.,81402371 to Y.J.,81902326 to X.W.,11971297 to R.W.);the Basic Frontier Scientific Research Program of the Chinese Academy of Sciences(ZDBS-LY-SM006 to H.J.);the International Cooperation Project of the Chinese Academy of Sciences(153D31KYSB20190035 to H.J.);the Science and Technology Commission of Shanghai Municipality(21ZR1470300to L.H.);the Youth Innovation Promotion Association,Chinese Academy of Sciences(Y919S31371 to X.W.);the Special Fund for Science and Technology Innovation Strategy of Guangdong Province(2021B0909050004 and 2021B0909060002 to L.C.);the Major Key Project of Peng Cheng Laboratory(PCL2021A12to L.C.);the JST Moonshot R&D(JPMJMS2021 to L.C.);the Science and Technology Commission of Shanghai Municipality(21ZR1470300 to L.H.);the Innovative Research Team of High-Level Local Universities in Shanghai(SSMUZLCX20180500 to H.J.)。 摘　　要：Human lung adenosquamous cell carcinoma(LUAS),containing both adenomatous and squamous pathologies,harbors strong plasticity and is significantly associated with poor prognosis.We established an up-to-date comprehensive genomic and transcriptomic landscape of LUAS in 109 Chinese specimens and demonstrated LUAS development via adeno-to-squamous transdifferentiation.Unsupervised transcriptomic clustering and dynamic network biomarker analysis identified an inflammatory subtype as the critical transition stage during LUAS development.Dynamic dysregulation of the counteracting lineage-specific transcription factors(TFs),containing adenomatous TFs NKX2-1 and FOXA2,and squamous TFs TP63 and SOX2,finely tuned the lineage transition via promoting CXCL3/5-mediated neutrophil infiltration.Genomic clustering identified the most malignant subtype featured with STK11-inactivation,and targeting LSD1 through genetic deletion or pharmacological inhibition almost eradicated STK11-deficient lung tumors.These data collectively uncover the comprehensive molecular landscape,oncogenic driver spectrum and therapeutic vulnerability of Chinese LUAS. 关 键 词：LUAS ALK fusion counteracting TF regulatory network CXCL3/CXCL5 LSD1
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