Tian Xiao
Yan Feng
Jinhua Yang
Chenchen Guo
Liang Hu
Hongbin Ji
a State Key Laboratory of Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China;
b Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China;
c Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China;
d Shenzhen Key Laboratory of Translational Medicine of Tumor, Department of Cell Biology and Genetics, Shenzhen University Health Sciences Center, Shenzhen, Guangdong 518060, China;
e University of Chinese Academy of Sciences, Beijing 100049, China;
f School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
Funds: the National Natural Science Foundation of China (81872312 to H.J., 82011540007 to H.J., 31621003 to H.J., 81402371 to Y.J.)
2020YFA0803300 to H.J.)
the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB19020201 to H.J.)
the National Basic Research Program of China (2017YFA0505501 to H.J.
This work was supported by the National Natural Science Foundation of China (82030083 to H.J., 81871875 to L.H.)
the International Cooperation Project of Chinese Academy of Sciences (153D31KYSB20190035 to H.J.).
the Basic Frontier Scientific Research Program of Chinese Academy of Science (ZDBS-LY-SM006 to H.J.)
Received Date: 2021-04-29
Accepted Date:2021-05-30
Rev Recd Date:2021-05-24
Publish Date:2021-07-20
Abstract
Abstract
Small cell lung cancer (SCLC) is the most aggressive lung cancer with high heterogeneity. Mouse SCLC cells derived from the Rb1L/L/Trp53L/L (RP) autochthonous mouse model grew as adhesion or suspension in cell culture, and the adhesion cells are defined as non-neuroendocrine (non-NE) SCLC cells. Here, we uncover the heterogenous subpopulations within the non-NE cells and referred to them as mesenchymal-like (Mes) and epithelial-like (Epi) SCLC cells. The Mes cells have increased capability to form colonies in soft agar and harbored stronger metastatic capability in vivo when compared with the Epi cells. Gene Set Enrichment Analysis reveals that the transforming growth factor (TGF)-β signaling is enriched in the Mes cells. Importantly, inhibition of the TGF-β signaling through ectopic expression of dominant-negative Tgfbr2 (Tgfbr2-DN) or treatment with Tgfbr1 inhibitor SD-208 consistently abrogates tumor metastasis in nude mouse allograft assays. Moreover, genetic deletion of Tgfbr2 or Smad4, the key components of the TGF-β signaling pathway, dramatically attenuates SCLC metastasis in the RP autochthonous mouse model. Collectively, our results uncover the high heterogeneity in non-NE SCLC cells and highlight an important role of TGF-β signaling in promoting SCLC metastasis.Keywords: Small cell lung cancer,
Heterogeneity,
Metastasis,
TGF-β signaling
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