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

Ji, h.; Jin, Y.; Zhao, Q.; Zhu, W.; Feng, Y.; Xiao, T.; Zhang, P.; Jiang, L.; Hou, Y.; Guo, C.; Huang, H.; Chen, Y.; Tong, X.; Cao, J.; Zhu, X.; Qin, J.; Gao, D.; Liu, X.-y.; Zhang, H.; Chen, L.; Thomas, R. K.; Wong, K.-K.; Wang, Y.; Hu, L.

doi:10.1101/2021.07.28.454244

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bioRxiv · 10.1101/2021.07.28.454244

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

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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.

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Ji, h., Jin, Y., Zhao, Q., Zhu, W., Feng, Y., Xiao, T., Zhang, P., Jiang, L., Hou, Y., Guo, C., Huang, H., Chen, Y., Tong, X., Cao, J., Zhu, X., Qin, J., Gao, D., Liu, X.-y., Zhang, H., Chen, L., Thomas, R. K., Wong, K.-K., Wang, Y., Hu, L.. 2021-07-29. Identification of TAZ as the essential molecular switch in orchestrating SCLC phenotypic transition and metastasis. https://doi.org/10.1101/2021.07.28.454244

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