This project aims to characterize and understand the contribution of tumor associated macrophages (TAMs) in the glioblastoma (GBM) microenvironment. In other tumor contexts, TAMs have been shown to closely resemble alternatively activated M2 macrophages and provide pro-tumorigenic factors to the tumor. Previous work in the lab demonstrates that two potential populations of TAMs are present in the tumor microenvironment: the brain resident microglia (MG) and bone marrow derived macrophages (BMDM). To understand the differences between the populations we utilized a bone marrow transplant model specifically labeling the TAM BMDMs with GFP, while the TAM MG remained unlabeled. This allowed for isolation and transcriptional characterization using Affymetrix arrays. Preliminary analysis demonstrates an enrichment of alternatively activated M2 markers in the TAM BMDM compared to TAM MG suggesting a functional difference between the two populations. My central hypotheses are: 1) the BMDM and MG populations of TAMs in GBM are differentially polarized, and 2) that this differential polarization impacts the development and progression of GBM in different manners. My long term goals are to understand which factors drive the differential M2 polarization of the TAMs, how this affects tumor progression, and which components are targetable for therapeutic intervention. The first specific aim will be to characterize the presence of M1 and M2 polarized TAM in vivo as well as the role that this polarization may confer using co-culture experiments. The second specific aim will investigate how M2 polarization may modulate tumor progression in vivo, with the goal of identifying the mechanisms that drive the differential polarization observed between the BMDMs and MG. The third specific aim will utilize computational methods to explore transcriptional networks in TAMs and develop gene expression signatures to aid the field in understanding the role of TAMs in tumor progression. The implications of this work extend beyond the glioma microenvironment offering insight into brain metastasis, other tumor sites, inflammatory macrophage biology and immune mediated neurodegenerative disorders.
The long-term goals of this project are to understand how specific cells of the immune system contribute to brain tumor progression and to identify the factors which determine if these cells are tumor promoting or working against the tumor. The research described here will also give insight into how inflammation is linked to tumor progression and neurodegenerative disorders.
|Sevenich, Lisa; Bowman, Robert L; Mason, Steven D et al. (2014) Analysis of tumour- and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S. Nat Cell Biol 16:876-88|
|Pyonteck, Stephanie M; Akkari, Leila; Schuhmacher, Alberto J et al. (2013) CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 19:1264-72|