title: Macrophage Ontogeny Underlies Differences in Tumor-Specific Education in Brain Malignancies.
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.
authors.affiliation: 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.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Bowman
authors.affiliation: 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.
authors.forename: Florian
authors.initials: F
authors.lastname: Klemm
authors.affiliation: 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.
authors.forename: Leila
authors.initials: L
authors.lastname: Akkari
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Pyonteck
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Sevenich
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Daniela F
authors.initials: DF
authors.lastname: Quail
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Surajit
authors.initials: S
authors.lastname: Dhara
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Kenishana
authors.initials: K
authors.lastname: Simpson
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Gardner
authors.affiliation: 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.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Iacobuzio-Donahue
authors.affiliation: Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Cameron W
authors.initials: CW
authors.lastname: Brennan
authors.affiliation: Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Viviane
authors.initials: V
authors.lastname: Tabar
authors.affiliation: Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Gutin
authors.affiliation: 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.
authors.forename: Johanna A
authors.initials: JA
authors.lastname: Joyce
mesh_terms: D000818:Animals; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D019070:Cell Lineage; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D005910:Glioma / Q000235:genetics / Q000473:pathology; D006801:Humans; D039441:Integrin alpha4 / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D017423:Sequence Analysis, RNA; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D014157:Transcription Factors; D039441:Integrin alpha4
keywords: CD49D; Macrophage; brain metastasis; glioma; microglia; tumor-associated macrophages