Project Details
Projekt
Impact of macrophage/microglia IL4R-activation on CNS-colonization
Applicant
Professor Dr. Tobias Pukrop
Subject Area
Pathology
Term
from 2017 to 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 242727105
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.
DFG Programme
Research Units
