Metastatic site-specific polarization of macrophages in intracranial breast cancer metastases.

// Nora Rippaus 1, * , David Taggart 1, * , Jennifer Williams 1 , Tereza Andreou 1 , Heiko Wurdak 1 , Krzysztof Wronski 2 , Mihaela Lorger 1 1 Institute of Cancer and Pathology, University of Leeds, St. James’s University Hospital, LS9 7TF Leeds, UK 2 Geneflow Ltd, Elmhurst, Lichfield, Staffordshire WS13 8EX, UK * These authors contributed equally to this work Correspondence to: Mihaela Lorger, email: M.Lorger@leeds.ac.uk Keywords: metastasis-associated macrophages, tumor-associated macrophages, breast cancer brain metastases, dural metastases, lymphotoxin β Received: January 28, 2016      Accepted: April 10, 2016      Published: May 18, 2016 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.