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.

小细胞肺癌 (SCLC) 是最具侵袭性的肺癌，具有高度异质性。来源于Rb1 ^L/L /Trp53 ^L/L (RP) 本土小鼠模型的小鼠 SCLC 细胞在细胞培养中以粘附或悬浮的形式生长，粘附细胞被定义为非神经内分泌 (non-NE) SCLC 细胞。在这里，我们发现了非 NE 细胞内的异质亚群，并将它们称为间充质样 (Mes) 和上皮样 (Epi) SCLC 细胞。Mes 细胞在软琼脂中形成集落的能力增强，并且在体内具有更强的转移能力与 Epi 细胞相比。基因集富集分析表明，转化生长因子 (TGF)-β 信号在 Mes 细胞中富集。重要的是，通过显性失活 Tgfbr2 (Tgfbr2-DN) 的异位表达或用 Tgfbr1 抑制剂 SD-208 治疗来抑制 TGF-β 信号传导，在裸鼠同种异体移植试验中始终消除肿瘤转移。此外， TGF-β 信号通路的关键成分Tgfbr2或Smad4的基因缺失显着减弱了 RP 本土小鼠模型中的 SCLC 转移。总的来说，我们的结果揭示了非 NE SCLC 细胞的高异质性，并强调了 TGF-β 信号传导在促进 SCLC 转移中的重要作用。