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

Robert L. Bowman, Florian Klemm, Leila Akkari, Stephanie M. Pyonteck, Lisa Sevenich, Daniela F. Quail, Surajit Dhara, Kenishana Simpson, Eric E. Gardner, Christine A. Iacobuzio-Donahue, Cameron W. Brennan, Viviane Tabar, Philip H. Gutin, Johanna A. Joyce

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2445-2459
Number of pages15
JournalCell Reports
Volume17
Issue number9
DOIs
StatePublished - Nov 22 2016

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Bowman, R. L., Klemm, F., Akkari, L., Pyonteck, S. M., Sevenich, L., Quail, D. F., Dhara, S., Simpson, K., Gardner, E. E., Iacobuzio-Donahue, C. A., Brennan, C. W., Tabar, V., Gutin, P. H., & Joyce, J. A. (2016). Macrophage Ontogeny Underlies Differences in Tumor-Specific Education in Brain Malignancies. Cell Reports, 17(9), 2445-2459. https://doi.org/10.1016/j.celrep.2016.10.052