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

Author:

Jin Yujuan123,Zhao Qiqi123,Zhu Weikang4,Feng Yan123,Xiao Tian5,Zhang Peng6,Jiang Liyan7,Hou Yingyong8,Guo Chenchen123,Huang Hsinyi123,Chen Yabin123,Tong Xinyuan123,Cao Jiayu123,Li Fei9,Zhu Xueliang12310,Qin Jun11,Gao Dong123,Liu Xin-Yuan123,Zhang Hua12ORCID,Chen Luonan123ORCID,Thomas Roman K13,Wong Kwok-Kin12,Zhang Lei12314,Wang Yong4,Hu Liang123ORCID,Ji Hongbin12314ORCID

Affiliation:

1. State Key Laboratory of Cell Biology

2. Shanghai Institute of Biochemistry and Cell Biology

3. Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; Shanghai200031, China

4. CEMS, NCMIS, MDIS, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing100190, China

5. Shenzhen Key Laboratory of Translational Medicine of Tumor, Department of Cell Biology and Genetics, Shenzhen University Health Sciences Center, Shenzhen, Guangdong, 518060, China

6. Shanghai pulmonary hospital, Tongji University, Shanghai, 200092, China

7. Shanghai chest hospital, 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, 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, China

12. Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, NY, NY 10016, USA

13. Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany. Department of Pathology, University Hospital Cologne, 50937Cologne, Germany

14. School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou310024, China

Abstract

Abstract Small cell lung cancer (SCLC) is a recalcitrant cancer featured with high metastasis. However, the exact cell type contributing to metastasis remains elusive. Using Rb1L/L/Trp53L/L mouse model, we identify the NCAMhiCD44lo/– subpopulation as SCLC metastasizing cell (SMC), which is progressively transitioned from non-metastasizing NCAMloCD44hi cell (Non-SMC). Integrative chromatin accessibility and gene expression profiling studies reveal an important role of SWI/SNF complex, and knockout of its central component, Brg1, significantly inhibits such phenotypic transition and metastasis. Mechanistically, TAZ is silenced by 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 key molecular switch in orchestrating SCLC phenotypic transition and metastasis.

Publisher

Oxford University Press (OUP)

Subject

Multidisciplinary

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