A mesenchymal-like subpopulation in non-neuroendocrine SCLC contributes to metastasis |
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| Affiliation: | 1. State Key Laboratory of Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China;2. Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China;3. Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China;4. Shenzhen Key Laboratory of Translational Medicine of Tumor, Department of Cell Biology and Genetics, Shenzhen University Health Sciences Center, Shenzhen, Guangdong 518060, China;5. University of Chinese Academy of Sciences, Beijing 100049, China;6. School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China;1. The State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China;2. Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China;1. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;2. The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA;1. School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang 150001, China;2. Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, China;3. Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China;4. Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, China;5. Department of Radiation and Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, 450 West Drive, Chapel Hill, NC 27599-7461, USA;6. Shenzhen Graduate School of Harbin Institute of Technology, Shenzhen 518055, China;1. Laboratory of Comparative Pathology, Department of Clinical Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818 Japan;2. Laboratory of Radiation Biology, Department of Applied Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818 Japan;3. Department of Pathology, Yale School of Medicine, New Haven, CT 06510, USA |
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| 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. |
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| Keywords: | Small cell lung cancer Heterogeneity Metastasis TGF-β signaling |
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