Small-cell lung cancer(SCLC)is a recalcitrant cancer characterized by high metastasis.However,the exact cell type contributing to metastasis remains elusive.Using a Rb1L/L/Trp53L/L mouse model,we identify the NCAMhiCD441o/-subpopulation as the SCLC metastasizing cell(SMC),which is progressively transitioned from the non-metastasizing NCAMloCD44hi cell(non-SMC).Integrative chromatin accessibility and gene expression profiling studies reveal the important role of the SWI/SNF complex,and knockout of its central component,Brgl,significantly inhibits such phenotypic transition and metastasis.Mechanistically,TAZ is silenced by the SWI/SNF complex during SCLC malignant progression,and its knockdown promotes SMC transition and metastasis.Importantly,ectopic TAZ expression reversely drives SMC-to-non-SMC transition and alleviates metastasis.Single-cell RNA-sequencing analyses identify SMC as the dominant subpopulation in human SCLC metastasis,and immunostaining data show a positive correlation between TAZ and patient prognosis.These data uncover high SCLC plasticity and identify TAZ as the key molecular switch in orchestrating SCLC phenotypic transition and metastasis.

Yujuan Jin;Qiqi Zhao;Weikang Zhu;Yan Feng;Tian Xiao;Peng Zhang;Liyan Jiang;Yingyong Hou;Chenchen Guo;Hsinyi Huang;Yabin Chen;Xinyuan Tong;Jiayu Cao;Fei Li;Xueliang Zhu;Jun Qin;Dong Gao;Xin-Yuan Liu;Hua Zhang;Luonan Chen;Roman K.Thomas;Kwok-Kin Wong;Lei Zhang;Yong Wang;Liang Hu;Hongbin Ji

State Key Laboratory of Cell Biology,Chinese Academy of Sciences,Shanghai 200031,China;Shanghai Institute of Biochemistry and Cell Biology,Chinese Academy of Sciences,Shanghai 200031,China;Center for Excellence in Molecular Cell Science,Chinese Academy of Sciences,Shanghai 200031,China;Center for Excellence in Mathematical Sciences,National Center for Mathematics and Interdisciplinary Sciences,Key Laboratory of Management,Decision and Information System,Hua Loo-Keng Center for Mathematical Sciences,Academy of Mathematics and Systems Science,Chinese Academy of Sciences,Beijing 100190,China;Shenzhen Key Laboratory of Translational Medicine of Tumor,Department of Cell Biology and Genetics,Shenzhen University Health Sciences Center,Shenzhen 518060,China;Shanghai Pulmonary Hospital,Tongji University,Shanghai 200092,China;Shanghai Chest Hospital,Shanghai Jiaotong University,Shanghai 200030,China;Zhongshan Hospital,Fudan University,Shanghai 200032,China;Department of Pathology,School of Basic Medical Sciences,Fudan University,Shanghai 200032,China;School of Life Science and Technology,Shanghai Tech University,Shanghai 200120,China;CAS Key Laboratory of Tissue Microenvironment and Tumor,CAS Center for Excellence in Molecular Cell Science,Shanghai Institute of Nutrition and Health Sciences,Chinese Academy of Sciences,Shanghai 200031,China;Laura and Isaac Perlmutter Cancer Center,New York University Langone Medical Center,New York,NY 10016,USA;School of Life Science,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou 310024,China;Department of Translational Genomics,Center of Integrated Oncology Cologne-Bonn,Medical Faculty,University of Cologne,Cologne 50931,Germany;Department of Pathology,University Hospital Cologne,Cologne 50937,Germany

国家科学评论（英文版）

[1]Yujuan Jin;Qiqi Zhao;Weikang Zhu;Yan Feng;Tian Xiao;Peng Zhang;Liyan Jiang;Yingyong Hou;Chenchen Guo;Hsinyi Huang;Yabin Chen;Xinyuan Tong;Jiayu Cao;Fei Li;Xueliang Zhu;Jun Qin;Dong Gao;Xin-Yuan Liu;Hua Zhang;Luonan Chen;Roman K.Thomas;Kwok-Kin Wong;Lei Zhang;Yong Wang;Liang Hu;Hongbin Ji-.Identification of TAZ as the essential molecular switch in orchestrating SCLC phenotypic transition and metastasis)[J].国家科学评论（英文版）,2022(07):10-24

Rb1L,Trp53L,NCAMhiCD441o,NCAMloCD44hi,Brgl

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