Neuronal mimicry mechanisms promote the growth of small-cell lung cancer in the brain [human astrocytes RNA-seq]

Small cell lung cancer (SCLC) is a fatal form of cancer that frequently metastasizes to the brain. Here we investigated the mechanisms allowing SCLC cells to grow in the unique brain microenvironment. We found that neuronal programs upregulated in SCLC cells during tumor progression and upon growth in the brain are critical for SCLC growth in the brain. Mechanistically, the presence of SCLC cells in the brain re-activates astrocytes, which in turn promote the survival of SCLC cells by secreting neuronal pro-survival factors such as SERPINE1. We also identified Reelin, a molecule produced by developing neurons to recruit astrocytes, as a molecule secreted by SCLC cells to recruit astrocytes to the tumor site and promote SCLC growth in the brain. Thus, SCLC cells co-opt mechanisms normally at play between astrocytes and neurons to promote SCLC growth in the brain. Targeting such developmental neuronal programs may help treat brain metastases. Overall design: 9 samples were analyzed: human astrocytes cultured alone (3) or co-cultured with human SCLC cell line NCI-H69 (3) or NCI-H82 (3)

小细胞肺癌（Small cell lung cancer, SCLC）是一种致死性恶性肿瘤，常发生脑转移。本研究旨在探究小细胞肺癌细胞能够在独特的脑微环境中定植生长的分子机制。我们发现，在肿瘤进展阶段及脑内定植过程中，小细胞肺癌细胞内上调的神经元相关基因表达程序，对于其在脑内的生长至关重要。从机制层面来看，脑内的小细胞肺癌细胞可重新激活星形胶质细胞（astrocyte），而后者可通过分泌SERPINE1等神经元存活促进因子，促进小细胞肺癌细胞的存活。我们还鉴定出Reelin蛋白（Reelin）：该分子原本由发育中的神经元分泌以招募星形胶质细胞，而小细胞肺癌细胞亦可通过分泌Reelin蛋白，将星形胶质细胞招募至肿瘤部位并促进自身在脑内的生长。综上，小细胞肺癌细胞劫持了星形胶质细胞与神经元之间正常发挥作用的调控机制，以此促进自身在脑内的生长。靶向此类发育阶段的神经元相关基因表达程序，或可为脑转移治疗提供新的干预思路。整体实验设计：本研究共分析9份样本，包括单独培养的人星形胶质细胞（3份），以及分别与小细胞肺癌细胞系NCI-H69（3份）或NCI-H82（3份）共培养的人星形胶质细胞。