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

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各个阶段起着至关重要的作用。因此，为了治疗或预防转移，必须研究播散性肿瘤细胞与转移器官微环境的相互作用。然而，大脑中神经胶质细胞在促进转移性生长中的作用尚不清楚。星形胶质细胞是一种胶质细胞，参与大脑的修复和瘢痕形成，并介导脑损伤后的神经炎症。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。利用小鼠自发性黑色素瘤脑转移模型，结合临床数据、器官型3D共培养系统和转录组分析，我们旨在通过转移相关的星形胶质细胞来表征炎症信号。我们将阐明星形胶质细胞形成和脑转移过程中炎症信号的功能重要性，并确定星形胶质细胞内可能作为新治疗靶点的关键调节因子。由于目前还没有有效的脑转移治疗方法，因此有必要确定在转移性脑组织定植的早期、限速步骤中发挥作用的分子因素。实现对星形胶质反应的控制可能被证明是防止脑转移性复发的一种新的治疗方法。

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.