Metabolically activated adipose tissue macrophages link obesity to triple-negative breast cancer

Payal Tiwari, Ariane Blank, Chang Cui, Kelly Q. Schoenfelt, Guolin Zhou, Yanfei Xu, Galina Khramtsova, Funmi Olopade, Ajay M. Shah, Seema A. Khan, Marsha Rich Rosner*, Lev Becker

*Corresponding author for this work

Research output: Contribution to journalArticle

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1345-1358
Number of pages14
JournalJournal of Experimental Medicine
Volume216
Issue number6
DOIs
StatePublished - Jun 1 2019

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Tiwari, P., Blank, A., Cui, C., Schoenfelt, K. Q., Zhou, G., Xu, Y., Khramtsova, G., Olopade, F., Shah, A. M., Khan, S. A., Rosner, M. R., & Becker, L. (2019). Metabolically activated adipose tissue macrophages link obesity to triple-negative breast cancer. Journal of Experimental Medicine, 216(6), 1345-1358. https://doi.org/10.1084/jem.20181616