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Cell Rep. 2016 Nov 22;17(9):2445-2459. doi: 10.1016/j.celrep.2016.10.052. Epub 2016 Nov 10.

Macrophage Ontogeny Underlies Differences in Tumor-Specific Education in Brain Malignancies.

Author information

1
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Gerstner Sloan Kettering Graduate School of Biomedical Science, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
2
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Oncology, University of Lausanne, 1066 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, 1066 Lausanne, Switzerland.
3
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
4
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
5
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
6
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
7
Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
8
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Oncology, University of Lausanne, 1066 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, 1066 Lausanne, Switzerland. Electronic address: johanna@joycelab.org.

Abstract

Extensive transcriptional and ontogenetic diversity exists among normal tissue-resident macrophages, with unique transcriptional profiles endowing the cells with tissue-specific functions. However, it is unknown whether the origins of different macrophage populations affect their roles in malignancy. Given potential artifacts associated with irradiation-based lineage tracing, it remains unclear if bone-marrow-derived macrophages (BMDMs) are present in tumors of the brain, a tissue with no homeostatic involvement of BMDMs. Here, we employed multiple models of murine brain malignancy and genetic lineage tracing to demonstrate that BMDMs are abundant in primary and metastatic brain tumors. Our data indicate that distinct transcriptional networks in brain-resident microglia and recruited BMDMs 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 microglia and BMDMs in primary and metastatic disease in mouse and human.

KEYWORDS:

CD49D; Macrophage; brain metastasis; glioma; microglia; tumor-associated macrophages

PMID:
27840052
PMCID:
PMC5450644
DOI:
10.1016/j.celrep.2016.10.052
[Indexed for MEDLINE]
Free PMC Article

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