Identification of TAZ as the essential molecular switch in orchestrating SCLC phenotypic transition and metastasis  

作　　者：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 KThomas Kwok-Kin Wong Lei Zhang Yong Wang Liang Hu Hongbin Ji 

机构地区：[1]State Key Laboratory of Cell Biology,Chinese Academy of Sciences,Shanghai 200031,China [2]Shanghai Institute of Biochemistry and Cell Biology,Chinese Academy of Sciences,Shanghai 200031,China [3]Center for Excellence in Molecular Cell Science,Chinese Academy of Sciences,Shanghai 200031,China [4]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 [5]Shenzhen Key Laboratory of Translational Medicine of Tumor,Department of Cell Biology and Genetics,Shenzhen University Health Sciences Center,Shenzhen 518060,China [6]Shanghai Pulmonary Hospital,Tongji University,Shanghai 200092,China [7]Shanghai Chest Hospital,Shanghai Jiaotong University,Shanghai 200030,China [8]Zhongshan Hospital,Fudan University,Shanghai 200032,China [9]Department of Pathology,School of Basic Medical Sciences,Fudan University,Shanghai 200032,China [10]School of Life Science and Technology,Shanghai Tech University,Shanghai 200120,China [11]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 [12]Laura and Isaac Perlmutter Cancer Center,New York University Langone Medical Center,New York,NY 10016,USA [13]Department of Translational Genomics,Center of Integrated Oncology Cologne-Bonn,Medical Faculty,University of Cologne,Cologne 50931,Germany [14]School of Life Science,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou 310024,China [15]Department of Pathology,University Hospital Cologne,Cologne 50937,Germany

出　　处：《National Science Review》2022年第7期10-24,共15页国家科学评论（英文版）

基　　金：the National Natural Science Foundation of China(81871875 and 82173340 to L.H.,82030083,81872312,82011540007 and 31621003 to H.J.,81402371 to Y.J.,12025107 to Y.W.);the National Basic Research Program of China(2017YFA0505501 and 2020YFA0803300 to H.J.);the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB19020201 to H.J.);the Basic Frontier Scientific Research Program of the Chinese Academy of Sciences(ZDBSLY-SM006 to H.J.);the International Cooperation Project of the Chinese Academy of Sciences(153D31KYSB20190035 to H.J.);the Innovative Research Team of High-Level Local Universities in Shanghai(SSMU-ZLCX20180500 to H.J.);the Science and Technology Commission of Shanghai Municipality(21ZR1470300 to L.H.).

摘　　要：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 Rb1^(L/L)/Trp53^(L/L) mouse model,we identify the NCAM^(hi)CD44^(lo/–) subpopulation as the SCLC metastasizing cell(SMC),which is progressively transitioned from the non-metastasizing NCAM^(lo)CD44^(hi) 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,Brg1,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.

关 键 词：small cell lung cancer SWI/SNF complex TAZ phenotypic transition METASTASIS 

分 类 号：R734.2[医药卫生—肿瘤]