神经肽VGF驱动肺癌细胞代谢可塑性促进其脑内生存的机制研究

肺癌具有脑特异性转移特征，具体机制尚不清楚。前期工作中利用基因测序及生信分析筛选到脑转移相关因子—神经肽VGF和HOXB9，分析提示二者可能存在转录调控关系；细胞学实验表明VGF可改变脑转移肺癌细胞内能量代谢模式及线粒体形态，与其生存活力相关。本项目拟利用不同实验模型（肺癌脑转移动物，活体外脑组织切片培养，体外细胞共培养）探讨：①VGF是否介导肺癌脑内定植过程；②VGF是否调控肺癌细胞代谢可塑性（代谢模式转变及线粒体动力学改变）维系其脑内生存及可能机制；③解析HOXB9调控VGF表达分子机制；④分析HOXB9、VGF及相关因子在临床肺癌原发癌灶及脑转移癌灶中表达模式异同，明确这些因子表达模式与脑转移临床关系，评价其作为肺癌脑转移风险预测因子的可能性。这些工作的完成可望为防治肺癌脑转移提供潜在干预靶点，也为“肿瘤可塑性介导器官特异性转移”提供新的实验佐证，具有一定的医学意义和理论研究价值。

A feature of metastasis is that different cancer types and subtypes display preferentially metastasize to specific organs, known as 'organotropism’. Lung cancer is the primary tumor that most commonly metastasizes to the brain. However, it is not very clear why lung cancer metastasize to the brain more frequently than others. In our previous study, genome-wide sequencing analyses of metastatic variants identified a nerve growth factor (NGF)-inducible transcript, VGF and HOXB9 as regulators of lung cancer metastasis to brain. The further transcriptome analysis of lung cancer from TCGA database indicated that the levels of VGF and HOXB9 were positively correlated with the morbidity and prognosis of patients with lung cancer metastases to brain. Furthermore, there might be a transcriptional regulation between HOXB9 and VGF. After that, the results from the assay of cellular functions revealed that VGF could induce the transformation of cell energy metabolism and mitochondrial morphological adaptations, which contributed to the survival of lung cancer after metastazing to brain. Based on these results, our projects will be focused in the role of VGF in metabolic plasticity of lung cancer cell metastasized to brain. In the presented study, we will construct the different experimental models, including experimental brain metastatic animal model, ex vivo brain slice culture and in vitro cellular co-culture system. Using these models, we will explore the following problems: the exact effects of VGF on brain colonization of lung cancer cell; the detailed mechanisms of VGF-induced metabolic plasticity of brain metastatic cell; the possible mechanisms of HOXB9-controlled the upregulation of VGF; and the potential clinical relevance of VGF and HOXB9 with lung cancer metastasis to brain. These works are necessary to improve a better understanding of lung cancer preferentially metastasize to brain, which might provide a potential therapeutic target for brain metastasis treatment. More importantly, these studies will highlight the importance of cancer cell plasticity in organ-specific metastasis.