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

By hongbin Ji, 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, Xueliang Zhu, Jun Qin, Dong Gao, Xin-yuan Liu, Hua Zhang, Luonan Chen, Roman K Thomas, Kwok-Kin Wong, Yong Wang, Liang Hu

Posted 29 Jul 2021
bioRxiv DOI: 10.1101/2021.07.28.454244

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.

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