Induction of interferon signaling and allograft inflammatory factor 1 in macrophages in a mouse model of breast cancer metastases

Wellcome Open Research

article

Wei Zheng¹  Dejian Zhao³  Hui Zhang¹  Prameladevi Chinnasamy¹  Nicholas Sibinga¹  Jeffrey W. Pollard¹ 

[1] Department of Developmental and Molecular Biology, Albert Einstein College of Medicine and Montefiore Medical Center;Division of Hematology and Oncology, Icahn School of Medicine at Mount Sinai;Yale Center for Genome Analysis, Yale University;MRC Centre for Reproductive Health, Queen’s Medical Research Institute, The University of Edinburgh

关键词: breast cancer;    metastasis;    macrophage;    interferon;    AIF1;    IBA1;    tumor microenvironment;   

DOI  :  10.12688/wellcomeopenres.16569.2

学科分类：内科医学

来源: Wellcome

【 摘 要 】

Background: Metastatic breast cancer cells recruit macrophages (metastasis-associated macrophages, or MAMs) to facilitate their seeding, survival and outgrowth. However, a comprehensive understanding of the gene expression program in MAMs and how this program contributes to metastasis remain elusive.Methods: We compared the transcriptomes of MAMs recruited to lung metastases and resident alveolar macrophages (RAMs) and identified a large variety of differentially expressed genes and their associated signaling pathways. Some of the changes were validated using qRT-PCR and immunofluorescence. To probe the functional relevance to metastatic growth, a gene-targeting mouse model of female mice in the C57BL6/J background was used to study allograft inflammatory factor 1 (AIF1, also known as ionized calcium-binding adapter molecule 1 or IBA1).Results: Interferon signaling is one of the most activated pathways in MAMs, with strong upregulation of multiple components of the pathway and a significant enrichment for the gene signatures of interferon-alpha-treated human macrophages.Aif1, an interferon-responsive gene that regulates multiple macrophage activities, was robustly induced in MAMs.Aif1 deficiency in MAMs, however, did not affect development of lung metastases, suggesting that AIF1 indicates MAM activation but is dispensable for regulating metastasis.Conclusions: The drastically different gene expression profile of MAMs as compared to RAMs suggests an important role in promoting metastatic growth. Dissection of the underlying mechanisms and functional validation of potential targets in the profile may provide novel therapeutic strategies for the treatment of metastatic diseases.

【 授权许可】

CC BY