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Macrophage ontogeny underlies differences in tumor-specific education in brain malignancies

ABSTRACT: Recent efforts have uncovered immense transcriptional and ontogenetic diversity among tissue-resident macrophages, each with their own transcriptional profile endowing the cell with its tissue-specific functions. However, it is currently unknown whether the origins of different macrophage populations may affect their roles in malignancy. Given potential artifacts associated with irradiation-based lineage tracing, it remains unclear if bone marrow-derived macrophages (BMDM) are even present in tumors of the brain, a tissue where there is no homeostatic involvement of peripherally-derived myeloid cells. Here, we employed multiple models of murine brain malignancy and genetic lineage tracing models to demonstrate that BMDM are indeed abundant in primary and metastatic brain tumors. Transcriptional profiling of tumor-associated BMDM and resident microglia showed that these cells acquire substantially different gene expression profiles. Our data suggest that transcriptional networks in each cell population are associated with tumor-mediated education, yet are also influenced by chromatin landscapes established before tumor initiation. Furthermore, we demonstrate that microglia specifically repress Itga4 (CD49D), enabling its utility as a discriminatory marker between brain-resident microglia and peripherally-derived macrophages in both primary and metastatic disease in mouse and human.

ORGANISM(S): Mus musculus

PROVIDER: GSE86573 | GEO | 2016/11/10

SECONDARY ACCESSION(S): PRJNA345301

REPOSITORIES: GEO

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Project description:Objective: Brain tumors (gliomas) contain large populations of infiltrating macrophages and recruited microglia, which in experimental murine glioma models promote tumor formation and progression. Among the barriers to understanding the contributions of these stromal elements to high-grade glioma (glioblastoma; GBM) biology is the relative paucity of tools to characterize infiltrating macrophages and resident microglia. In this study, we leveraged multiple RNA analysis platforms to identify new monocyte markers relevant to GBM patient outcome. Methods: High-confidence lists of mouse resident microglia- and bone marrow-derived macrophage-specific transcripts were generated using converging RNA-seq and microarray technologies and validated using qRT-PCR and flow cytometry. Expression of select cell surface markers was analyzed in brain-infiltrating macrophages and resident microglia in an induced GBM mouse model, while allogeneic bone marrow transplantation was performed to trace the origins of infiltrating and resident macrophages. Glioma tissue microarrays were examined by immunohistochemistry, and the Gene Expression Omnibus (GEO) database was queried to determine the prognostic value of identified microglia biomarkers in human GBM. Results: We generated a unique catalog of differentially-expressed bone marrow-derived monocyte and resident microglia transcripts, and demonstrated that brain-infiltrating macrophages acquire F11R expression in GBM and following bone-marrow transplantation. Moreover, mononuclear cell F11R expression positively correlates with human high-grade glioma and additionally serves as a biomarker for GBM patient survival, regardless of GBM molecular subtype. Significance: These studies establish F11R as a novel monocyte prognostic marker for GBM critical for defining a subpopulation of stromal cells for future potential therapeutic intervention. Total RNA was isolated from three independently-generated sets of flow sorted bone marrow monocytes (CD11b+ CD45high CD115+ Ly6G- cells) and brainstem microglia (CD11b+ CD45low CD115low Ly6G- cells) for Illumina RNA-Seq, and two additional pools were subsequently generated and submitted for Affymetrix Mouse Exon 1.0ST microarray. Two of the RNA-Seq samples were additionally analyzed by the microarray, for a total of 6 samples (3 monocyte, 3 microglia) in each platform. Data outputs were analyzed by two analysis methods each (RNA-Seq data: ALEXA-Seq and Cufflinks; microarray data: Partek and Aroma). All four lists were merged into a new high-confidence gene list of transcripts that were significantly differentially expressed (DE) in three out of the four analyses. In this dataset, we include exon expression data obtained from flow sorted mouse bone marrow monocytes and brainstem microglia.

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Macrophage ontogeny underlies differences in tumor-specific education in brain malignancies

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