# Metabolically active macrophages: a novel link between obesity and triple negative breast cancer

> **NIH NIH K00** · DANA-FARBER CANCER INST · 2020 · $90,422

## Abstract

Metabolically Active Macrophages: A novel mechanistic link between obesity and TNBC
 Triple negative breast cancer (TNBC) patients have an extremely poor prognosis due to their high
metastatic potential and lack of targeted drug therapies. Emerging epidemiological data suggest that obesity is
strongly linked to the incidence and severity of TNBC. Thus, understanding the biological processes that link
obesity and TNBC has important clinical applications for prognosis and treatment.
 Previous study showed that obesity promote tumor burden in C3Tag mouse model. However, mechanisms
by which obesity potentiates TNBC progression are incompletely understood. One clue to its action is that
obesity causes chronic inflammation, and adipose macrophages (ATMs) accumulation, which are a key source
of this inflammation. While it is well established that tumor-associated macrophages (TAMs) are key effector
cells that promote breast cancer, role of ATMs on tumorigenesis has largely been ignored. ATMs are an
attractive mechanistic link between obesity and TNBC as ATMs are the predominant type of macrophage in
the breast during early tumorigenesis. This raises the possibility that ATMs play an important role in tumor
progression.
 Here we show that metabolic dysfunction promotes a mechanistically distinct pro-inflammatory phenotype
(metabolic activation; MMe) in breast adipose tissue macrophages isolated from obese women and express
cell surface markers of MMe (CD36, ABCA1), but not M1 (CD38, CD319, CD274), macrophages. Furthermore,
treating naïve macrophages with media conditioned by human breast adipose tissue from an obese subject
(BMI = 37), but not a lean subject (BMI = 19), induced genes diagnostic of the MMe phenotype. We further
demonstrated that pre-treating human TNBC cells (MDA-MB-231) with conditioned media derived from MMe
macrophages promotes colony formation and invasion in vitro, and intravasation of cancer cells into the blood
in vivo. Moreover, pre-treated cancer cells showed a two fold increase in the expression of stem-like cell
markers (CD90, OCT4, SOX2 and NANOG). Remarkably, we saw the same effect on ‘stemness’ of tumor cells
in obese mice compared to lean mice. Based on these findings we hypothesize that obesity-induced changes
to mammary adipose tissue reprogram macrophages to a MMe phenotype that potentiates TNBC initiation and
metastasis.
 In the proposed work, we would determine the mechanism by which MMe macrophages promote TNBC
progression (aim1) and their contribution in promoting obesity-associated TNBC (aim 2). In aim 1, we will test
the hypothesis that inflammatory cytokines secreted by MMe macrophages are responsible for their pro-
tumorigenic effect. Two test this we will deplete inflammatory cytokines in MMe macrophage conditioned media
using two approaches: i). Genetic knockout (TLR2-/- and NOX2-/-) macrophages that inhibit inflammatory
cytokine expression in MMe macrophages. ii). Neutralizing antibodies against inflammatory c...

## Key facts

- **NIH application ID:** 9841364
- **Project number:** 5K00CA212477-04
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Payal Tiwari
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $90,422
- **Award type:** 5
- **Project period:** 2018-12-21 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841364

## Citation

> US National Institutes of Health, RePORTER application 9841364, Metabolically active macrophages: a novel link between obesity and triple negative breast cancer (5K00CA212477-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9841364. Licensed CC0.

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