title: Metastatic site-specific polarization of macrophages in intracranial breast cancer metastases.
abstract: In contrast to primary tumors, the understanding of macrophages within metastases is very limited. In order to compare macrophage phenotypes between different metastatic sites, we established a pre-clinical mouse model of intracranial breast cancer metastasis in which cancer lesions develop simultaneously within the brain parenchyma and the dura. This mimics a situation that is commonly occurring in the clinic. Flow cytometry analysis revealed significant differences in the activation state of metastasis-associated macrophages (MAMs) at the two locations. Concurrently, gene expression analysis identified significant differences in molecular profiles of cancer cells that have metastasized to the brain parenchyma as compared to the dura. This included differences in inflammation-related pathways, NF-kB1 activity and cytokine profiles. The most significantly upregulated cytokine in brain parenchyma- versus dura-derived cancer cells was Lymphotoxin β and a gain-of-function approach demonstrated a direct involvement of this factor in the M2 polarization of parenchymal MAMs. This established a link between metastatic site-specific properties of cancer cells and the MAM activation state.
authors.affiliation: Institute of Cancer and Pathology, University of Leeds, St. James's University Hospital, LS9 7TF Leeds, UK.
authors.forename: Nora
authors.initials: N
authors.lastname: Rippaus
authors.affiliation: Institute of Cancer and Pathology, University of Leeds, St. James's University Hospital, LS9 7TF Leeds, UK.
authors.forename: David
authors.initials: D
authors.lastname: Taggart
authors.affiliation: Institute of Cancer and Pathology, University of Leeds, St. James's University Hospital, LS9 7TF Leeds, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Williams
authors.affiliation: Institute of Cancer and Pathology, University of Leeds, St. James's University Hospital, LS9 7TF Leeds, UK.
authors.forename: Tereza
authors.initials: T
authors.lastname: Andreou
authors.affiliation: Institute of Cancer and Pathology, University of Leeds, St. James's University Hospital, LS9 7TF Leeds, UK.
authors.forename: Heiko
authors.initials: H
authors.lastname: Wurdak
authors.affiliation: Geneflow Ltd, Elmhurst, Lichfield, Staffordshire WS13 8EX, UK.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Wronski
authors.affiliation: Institute of Cancer and Pathology, University of Leeds, St. James's University Hospital, LS9 7TF Leeds, UK.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Lorger
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D016764:Cell Polarity; D004660:Encephalitis / Q000473:pathology; D005260:Female; D006801:Humans; D008264:Macrophages / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009928:Organ Specificity; D059016:Tumor Microenvironment / Q000276:immunology
keywords: breast cancer brain metastases; dural metastases; lymphotoxin β; metastasis-associated macrophages; tumor-associated macrophages