小细胞肺癌（SCLC）具有对脑特异性转移的特点，具体机制尚不清楚。前期发现，SCLC可以将细胞膜下蛋白Annexin A1外分泌到细胞外，介导脑转移的发生。进一步利用蛋白质质谱分析，在SCLC分泌的外泌体中筛选到能够与其结合的S100家族蛋白——S100A16，初步结果提示其与SCLC脑转移有关。本项目拟研究：①明确SCLC外泌体中S100A16与SCLC脑转移的关系；②探明SCLC外泌体中S100A16介导SCLC与BBB相互作用迁移入脑的过程；③解析SCLC 外泌体中S100A16如何完成细胞间信息的传递以调控BBB组成细胞功能，帮助SCLC迁移入脑；④分析SCLC患者血清外泌体中S100A16在脑转移中的临床意义，评价其作为脑转移风险预测因子的可能性。本项目的完成可为“外泌体介导肿瘤器官特异性转移”提供实验佐证，丰富SCLC脑转移机制的研究，有望为防治SCLC脑转移提供潜在作用靶点。

Small cell lung cancer (SCLC) is the most aggressive histologic subtype of lung cancer, with a strong predilection for metastasizing early. However, the cellular and molecular basis of SCLC brain metastasis is poorly known. Some recent studies revealed that brain microvasculature was the primary soil for metastatic tumor cell attachment and growth in the brain. We previously found that SCLC cells acted on human brain microvascular endothelial cells (HBMEC) to induce disassembly of TJ that leading to increased endothelial permeability and SCLC cells transendothelial migration. These data suggested that brain microvasculature might play an important role in the SCLC extravasation into the brain parenchyma. Therefore, we compare the protein expression profile in exosome derived from SCLC cell co-cultured with HBMEC by protein mass spectrometry and S100A16 was identified as a candidate protein. Further results showed that S100A16 in SCLC exosome was associated with SCLC metastasis to the brain. Based on these results, our projects will be focused in the role of S100A16 of SCLC exosome in SCLC migration across the blood brain barrier and metastasis to the brain, including S100A16 potential clinical relevance, the detailed effects of S100A16 in SCLC exosome on the SCLC metastasis to brain. Finally, the possibility of S100A16 in SCLC exosome as an early warning factor in SCLC metastasis to brain will be evaluated by the detection of a large number of clinical samples. These works are necessary to improve a better understanding of the mechanisms of SCLC brain metastasis and provide a potential therapeutic target for SCLC brain metastasis. More importantly, these studies will provide the strong evidence to verify the theory of exosome-mediated organotropic metastasis.