An ecosystem mimicking brain development promotes metastatic growth of SCLC in the brain. An ecosystem mimicking brain development promotes metastatic growth of SCLC in the brain

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: 6 samples were analyzed: brain stromal cells isolated from different regions of SCLC brain allografts (2 replicates) and sham injection control (2 replicates)

小细胞肺癌（Small Cell Lung Cancer, SCLC）是一类致死性癌症，常发生脑转移。本研究探究了小细胞肺癌细胞能够在独特脑微环境中增殖的机制。我们发现，在肿瘤进展过程中以及在脑内增殖时，小细胞肺癌细胞上调的神经元程序，对于其在脑内的生长至关重要。从机制层面分析，小细胞肺癌细胞在脑内的存在会重新激活星形胶质细胞（astrocytes），而星形胶质细胞可通过分泌诸如丝氨酸蛋白酶抑制剂E1（SERPINE1）这类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——一种由发育中的神经元产生以招募星形胶质细胞的分子——可由小细胞肺癌细胞分泌，进而将星形胶质细胞招募至肿瘤部位并促进小细胞肺癌在脑内的生长。因此，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，以促进其在脑内的生长。靶向此类发育性神经元程序或可为脑转移瘤的治疗提供新思路。实验设计：共分析6份样本：从小细胞肺癌脑异体移植瘤不同区域分离的脑基质细胞（2个生物学重复），以及假注射对照组样本（2个生物学重复）