Characterizing the functional role of astrogliosis and neuroinflammation in melanoma brainmetastasis.

表征星形胶质细胞增生和神经炎症在黑色素瘤脑转移中的功能作用。

• 批准号: 350030746
• 负责人: Professor Dr. Tobias Pukrop
• 金额: --
• 依托单位: Klinik und Poliklinik für Innere Medizin III
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/350030746?language=en
• 关键词: Characterizing; functional; role; astrogliosis; neuroinflammation

The major cause of melanoma mortality is metastasis to distant organs, frequently to the brain. The microenvironment plays a critical role in all stages of tumorigenesis and metastasis. Therefore, in order to cure or prevent metastasis, the interactions of disseminated tumor cells with the microenvironment of the metastatic organ have to be studied. Nevertheless, the role of glial cells in the brain in facilitating metastatic growth is poorly understood. Astrocytes are glial cells that participate in repair and scarring of the brain, and mediate neuroinflammation in response to brain injury. Astrocytes are activated during brain metastasis. However, the role of astrocytes and neuroinflammationin facilitating melanoma brain metastasis is unknown. Using mouse models of spontaneous melanoma brain metastasis, combined with clinical data, organotypic 3D coculture systems and transcriptome profiling, we aim to characterize inflammatory signaling by metastases associated astrocytes. We will elucidate the functional importance of astrogliosis and inflammatory signaling during brain metastasis and determine key regulators within astrocytes that may serve as novel therapeutic targets. Since there are currently no efficient therapies for brain metastasis, it is essential to identify molecular factors that play a role during the early, rate-limiting steps of metastatic colonization of the brain tissue. Achieving control on the astrogliosis response might prove as a novel therapeutic approach to prevent brain metastatic relapse.

黑色素瘤死亡的主要原因是转移到远处器官，经常转移到大脑。微环境在肿瘤发生和转移的所有阶段都起着关键作用。因此，为了治愈或预防转移，必须研究播散的肿瘤细胞与转移器官微环境的相互作用。然而，脑中胶质细胞在促进转移性生长中的作用知之甚少。星形胶质细胞是参与脑的修复和瘢痕形成的神经胶质细胞，并且介导响应于脑损伤的神经炎症。星形胶质细胞在脑转移过程中被激活。然而，星形胶质细胞和神经炎症在促进黑色素瘤脑转移中的作用尚不清楚。使用自发性黑色素瘤脑转移的小鼠模型，结合临床数据、器官型3D共培养系统和转录组分析，我们的目的是表征转移相关星形胶质细胞的炎症信号传导。我们将阐明脑转移过程中星形胶质细胞增生和炎症信号的功能重要性，并确定星形胶质细胞内的关键调节因子，这些调节因子可能作为新的治疗靶点。由于目前还没有有效的治疗脑转移的方法，它是必不可少的，以确定在脑组织的转移性定植的早期，限速步骤中发挥作用的分子因子。实现对星形胶质细胞增生反应的控制可能被证明是预防脑转移复发的一种新的治疗方法。