Impact of macrophage/microglia IL4R-activation on CNS-colonization

乳腺癌脑转移不仅严重影响患者的生活质量，而且预后严重，中位生存期为4~5.5个月。转移的最后一步，即定植，是一个多阶段的过程，可细分为：癌细胞进入转移器官后存活；形成微转移；恢复生长；大转移；超越宿主组织；在转移器官中扩散，最后器官破坏。最重要的是，它是整个转移级联反应的限速步骤。在中枢神经系统中，第一道防线是由小胶质细胞和星形胶质细胞组成的；然而，它在中枢神经系统定植过程中的作用却鲜为人知。到目前为止，我们知道在大脑播种后，小胶质细胞和星形胶质细胞立即被吸引并与入侵者共存。这迫使癌细胞在到达后不久适应这种外来的微环境和微环境。有趣的是，大多数到达的癌细胞无法在接下来的几个小时到几天内存活，只有少数开始重新生长。然而，癌细胞如何与胶质细胞相互作用，它们如何通信，以及在定植过程中参与这种相互作用的途径或信号几乎是未知的。最近，我们发现IL4R信号是单核细胞来源的巨噬细胞(MDM)/小胶质细胞定植促进表型的主要调节因子。根据这些发现，我们的目标是在DFG-FOR2127的第二个资助期的框架内，研究IL4R信号在MDM和小胶质细胞在大脑定植期间的影响。因此，我们将使用mdm/小胶质细胞特异性IL4rα(-/-)模型，通过立体定向注射研究各种同基因乳腺癌细胞系的定植过程。此外，我们将使用不同的共培养模型，并将研究IL4信号在巨噬细胞与乳腺癌细胞通讯中的影响。这些实验将有助于更好地理解这一非常复杂的中枢神经系统定植过程，以及乳腺癌细胞对外来微环境的适应。此外，我们将研究IL4信号在这一致命的转移过程中作为潜在的治疗靶点。

Brain metastases of breast cancer have not only significant impact on the quality of live (QoL), but also result in a fatal prognosis with a median overall survival (OS) ranging from 4 to 5.5 months. The final step of metastasis itself, the colonization, is a multi-phase process which can be subdivided into; survival of the carcinoma cells upon entry of the metastatic organ; formation of a micro-metastasis; reactivation of growth; macro-metastasis; overtaking the host tissue; the dissemination in the metastatic organ and finally the organ-destruction. Most important, it is the rate-limiting step of the whole metastatic cascade. In the CNS the first-line of defence is composed of microglia and astrocytes; however, its impact during CNS-colonization is barely understood. Up to date we know that after seeding of the brain microglia together with astrocytes immediately get attracted and co-localize with the intruders. This forces the carcinoma cells to adapt to this foreign microenvironment and micro-milieu shortly after arrival. Interestingly, the majority of the arriving cancer cells do not survive the next hours to days and only a few start to regrowth. However, how the carcinoma cells interact with the glial cells, how they communicate and which pathways or signals are involved in this interaction during the colonization are almost unknown. Recently, we identified IL4R-signaling as master regulator of the monocyte-derived macrophages (MDM)/microglia colonization-promoting phenotypes. In line with these findings we aim to investigate the impact of IL4R-signaling in MDM and microglia during colonization of the brain in the framework of the second funding period of the DFG-FOR2127. Therefore we will use MDM/microglia specific IL4rα(-/-) models and study the colonization process of various syngeneic breast cancer cell lines by stereotactical injection. Additionally we will use different co-culture models and will investigate the impact of IL4-signaling in the communication of the macrophages with breast cancer cells. These experiments will lead to a better understanding of this very complex process of CNS-colonization and of the adaption to a foreign microenvironment of the breast cancer cells. Additionally, we will investigate the IL4-signaling as potential therapeutic target during this fatal step of metastasis.