A mesenchymal-like subpopulation in non-neuroendocrine SCLC contributes to metastasis

Small cell lung cancer (SCLC) is the most aggressive lung cancer with high heterogeneity. Mouse SCLC cells derived from the Rb1^L/L/Trp53^L/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.