肺神经内分泌肿瘤细胞的亚型特异性分泌组学特征。

Subtype-specific secretomic characterization of pulmonary neuroendocrine tumor cells.

机构信息

Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, 75390, TX, USA.

Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, 75390, TX, USA.

出版信息

Nat Commun. 2019 Jul 19;10(1):3201. doi: 10.1038/s41467-019-11153-5.

Pulmonary neuroendocrine (NE) cancer, including small cell lung cancer (SCLC), is a particularly aggressive malignancy. The lineage-specific transcription factors Achaete-scute homolog 1 (ASCL1), NEUROD1 and POU2F3 have been reported to identify the different subtypes of pulmonary NE cancers. Using a large-scale mass spectrometric approach, here we perform quantitative secretome analysis in 13 cell lines that signify the different NE lung cancer subtypes. We quantify 1,626 proteins and identify IGFBP5 as a secreted marker for ASCL1 SCLC. ASCL1 binds to the E-box elements in IGFBP5 and directly regulates its transcription. Knockdown of ASCL1 decreases IGFBP5 expression, which, in turn, leads to hyperactivation of IGF-1R signaling. Pharmacological co-targeting of ASCL1 and IGF-1R results in markedly synergistic effects in ASCL1 SCLC in vitro and in mouse models. We expect that this secretome resource will provide the foundation for future mechanistic and biomarker discovery studies, helping to delineate the molecular underpinnings of pulmonary NE tumors.

肺神经内分泌（NE）癌，包括小细胞肺癌（SCLC），是一种特别具有侵袭性的恶性肿瘤。谱系特异性转录因子 Achaete-scute 同源物 1（ASCL1）、NEUROD1 和 POU2F3 已被报道可识别不同亚型的肺 NE 癌。在这里，我们使用大规模质谱分析方法，对代表不同 NE 肺癌亚型的 13 种细胞系进行定量分泌组分析。我们定量分析了 1626 种蛋白质，并确定 IGFBP5 是 ASCL1 SCLC 的分泌标志物。ASCL1 结合 IGFBP5 的 E 盒元件，并直接调节其转录。ASCL1 的敲低降低了 IGFBP5 的表达，进而导致 IGF-1R 信号的过度激活。ASCL1 和 IGF-1R 的药理学共同靶向在体外和小鼠模型中对 ASCL1 SCLC 具有显著的协同作用。我们期望这个分泌组资源将为未来的机制和生物标志物发现研究提供基础，有助于描绘肺 NE 肿瘤的分子基础。