Identification of TAZ as the essential 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

doi:10.1093/nsr/nwab232

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

Natl Sci Rev. 2022 Jan 4;9(7):nwab232. doi: 10.1093/nsr/nwab232. eCollection 2022 Jul.

Authors

Yujuan Jin¹, Qiqi Zhao¹, Weikang Zhu², Yan Feng¹, Tian Xiao³, Peng Zhang⁴, Liyan Jiang⁵, Yingyong Hou⁶, Chenchen Guo¹, Hsinyi Huang¹, Yabin Chen¹, Xinyuan Tong¹, Jiayu Cao¹, Fei Li⁷, Xueliang Zhu¹, Jun Qin⁸, Dong Gao¹, Xin-Yuan Liu¹, Hua Zhang⁹, Luonan Chen¹, Roman K Thomas¹⁰, Kwok-Kin Wong⁹, Lei Zhang¹, Yong Wang², Liang Hu¹, Hongbin Ji¹

Affiliations

¹ State Key Laboratory of Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
² 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.
³ Shenzhen Key Laboratory of Translational Medicine of Tumor, Department of Cell Biology and Genetics, Shenzhen University Health Sciences Center, Shenzhen 518060, China.
⁴ Shanghai Pulmonary Hospital, Tongji University, Shanghai 200092, China.
⁵ Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200030, China.
⁶ Zhongshan Hospital, Fudan University, Shanghai 200032, China.
⁷ Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
⁸ 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.
⁹ Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA.
¹⁰ Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne 50931, Germany.

Abstract

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^hiCD44^lo/- subpopulation as the SCLC metastasizing cell (SMC), which is progressively transitioned from the non-metastasizing NCAM^loCD44^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.

Keywords: SWI/SNF complex; TAZ; metastasis; phenotypic transition; small cell lung cancer.