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

黑色素瘤死亡的主要原因是远处器官的转移，通常是大脑转移。微环境在肿瘤发生和转移的各个阶段都起着关键作用。因此，为了治疗或防止转移，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，脑内神经胶质细胞在促进转移生长中的作用还知之甚少。星形胶质细胞是一种神经胶质细胞，参与大脑的修复和疤痕形成，并在脑损伤后介导神经炎症反应。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图谱，我们的目标是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和炎症信号在脑转移中的功能重要性，并确定星形胶质细胞内的关键调控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，因此确定在脑组织转移定植的早期限速步骤中起作用的分子因素是至关重要的。控制星形胶质细胞的反应可能被证明是预防脑转移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.