Metabolically activated adipose tissue macrophages link obesity to triple-negative breast cancer
Year: 2019
Type: article
Abstract: Obesity is associated with increased incidence and severity of triple-negative breast cancer (TNBC); however, mechanisms underlying this relationship are incompletely understood. Here, we show that obesity reprograms mammary adipose tissue macrophages to a pro-inflammatory metabolically activated phenotype (MMe) that alters the niche to support tumor formation. Unlike pro-inflammatory M1 macrophages that antagonize tumorigenesis, MMe macrophages are pro-tumorigenic and represent the dominant macrophage phenotype in mammary adipose tissue of obese humans and mice. MMe macrophages release IL-6 in an NADPH oxidase 2 (NOX2)–dependent manner, which signals through glycoprotein 130 (GP130) on TNBC cells to promote stem-like properties including tumor formation. Deleting Nox2 in myeloid cells or depleting GP130 in TNBC cells attenuates obesity-augmented TNBC stemness. Moreover, weight loss reverses the effects of obesity on MMe macrophage inflammation and TNBC tumor formation. Our studies implicate MMe macrophage accumulation in mammary adipose tissue as a mechanism for promoting TNBC stemness and tumorigenesis during obesity.
DOI: 10.1084/jem.20181616
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Funders: Avon Foundation for Women, Cancer Research Foundation, University of Chicago, National Institute for Health and Care Research, British Heart Foundation, King's College London, National Institutes of Health, Menzies Centre for Australian Studies, King's College London, University of London, Guy's and St Thomas' NHS Foundation Trust, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: Tumor-stromal interactions as targets of tumor metastasis suppressors, Metabolically active macrophages: a novel link between obesity and triple negative breast cancer, Redox-regulated adaptive pathways in heart failure (renewal), 'Metabolically Activated' Macrophages in Obesity and Insulin Resistance, SIRT6 and lysine fatty acylation in macrophage inflammation, Diabetes Research and Training Center
OpenAlex ID: W2943677497