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Interferon Regulatory Factor-8 (IRF8) Expression in Macrophages Governs an Anti-Metastatic Program in Breast Cancer

ABSTRACT: High macrophage infiltration in cancer is associated with reduced survival in animal models and in patients. This reflects a shift in the macrophage response from a tumor-suppressive to tumor-supportive program governed by transcriptional events regulated by the inflammatory milieu. Although several transcription factors are known to drive a pro-metastatic program, those that govern an anti-metastatic program are less understood. Interferon regulatory factor-8 (IRF8) is integral for macrophage responses against infections. Using a genetic loss-of-function approach, we tested the hypothesis that IRF8 expression in macrophages governs their capacity to inhibit metastasis. We found that: 1) metastasis was significantly increased in mice with IRF8-deficient macrophages; 2) IRF8-deficient macrophages displayed a neutrophil-like program enriched for metastasis-associated genes; and 3) lower IRF8 expression correlated with reduced survival in human breast cancer and melanoma with high or low macrophage infiltration. These data demonstrate a previously unrecognized role for IRF8 in macrophage biology to control metastasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE116904 | GEO | 2019/01/28

REPOSITORIES: GEO

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Project description:IThe transcription factor (TF) interferon regulatory factor 8 (IRF8) controls both developmental and inflammatory stimulus-inducible genes in macrophages, but the mechanisms underlying these two different functions are largely unknown. One possibility is that these different roles are linked to the ability of IRF8 to bind alternative DNA sequences. We found that IRF8 is recruited to distinct sets of DNA consensus sequences before and after lipopolysaccharide (LPS) stimulation. In resting cells, IRF8 was mainly bound to composite sites together with the master regulator of myeloid development PU.1. Basal IRF8M-bM-^@M-^SPU.1 binding maintained the expression of a broad panel of genes essential for macrophage functions (such as microbial recognition and response to purines) and contributed to basal expression of many LPS-inducible genes. After LPS stimulation, increased expression of IRF8, other IRFs, and AP-1 family TFs enabled IRF8 binding to thousands of additional regions containing low-affinity multimerized IRF sites and composite IRFM-bM-^@M-^SAP-1 sites, which were not premarked by PU.1 and did not contribute to the basal IRF8 cistrome. While constitutively expressed IRF8-dependent genes contained only sites mediating basal IRF8/PU.1 recruitment, inducible IRF8-dependent genes contained variable combinations of constitutive and inducible sites. Overall, these data show at the genome scale how the same TF can be linked to constitutive and inducible gene regulation via distinct combinations of alternative DNA-binding sites. Bone marrow cells isolated from C57BL/6 or BXH2/TyJ mice were plated in 10 cm plates in 5ml of BM-medium (high glucose DMEM supplemented with 20% low endotoxin fetal bovine serum, 30% L929-conditioned medium, 1% glutamine, 1%, Pen/Strep, 0.5% Sodium Pyruvate, 0.1% M-NM-2-mercaptoethanol). Cultures were fed with 2.5 ml of fresh medium every two days. Macrophages were subjected to different treatment (see individual samples for details). Total RNA was extracted from 5x106 cells using RNAeasy kit (Qiagen). Libraries were prepared from 1-2 M-BM-5g of RNA, after oligo-dT selection, using the TruSeq RNA sample preparation kit (Illumina).

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Interferon Regulatory Factor-8 (IRF8) Expression in Macrophages Governs an Anti-Metastatic Program in Breast Cancer

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