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 journalArticlepeer-review

23 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

  • Medicine(all)

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