FABP4-mediated lipid accumulation and lipolysis in tumor associated macrophages promote breast cancer metastasis

Abstract

A high density of tumor-associated macrophages (TAMs) is associated with poorer prognosis and survival in breast cancer patients. Recent studies have shown that lipid accumulation in TAMs can promote tumor growth and metastasis in various models. However, the specific molecular mechanisms that drive lipid accumulation and tumor progression in TAMs remain largely unknown. Herein, we demonstrated that unsaturated fatty acids (FAs), unlike saturated ones, are more likely to form lipid droplets in macrophages. Specifically, unsaturated FAs, including linoleic acids (LA), activate the FABP4/CEBP pathway, leading to triglyceride synthesis and lipid droplet formation. Furthermore, FABP4 enhances lipolysis and FA utilization by breast cancer cells, which promotes cancer cell migration in vitro and metastasis in vivo. Notably, a deficiency of FABP4 in macrophages significantly reduces LA-induced lipid metabolism. Therefore, our findings suggest FABP4 as a crucial lipid messenger that facilitates unsaturated FA-mediated lipid accumulation and lipolysis in TAMs, thus contributing to the metastasis of breast cancer. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC="FIGDIR/small/601733v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@7cba6dorg.highwire.dtl.DTLVardef@b37fb2org.highwire.dtl.DTLVardef@84aa8forg.highwire.dtl.DTLVardef@1d9bda2_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIUnlike saturated fatty acids, unsaturated fatty acids preferentially promote lipid droplet formation in macrophages. C_LIO_LIUnsaturated fatty acids activate the FABP4/CEBP axis for neutral lipid biosynthesis in macrophages C_LIO_LIDeficiency of FABP4 compromised unsaturated fatty acid-mediated lipid accumulation and utilization in macrophages C_LIO_LIFABP4-mediated lipid metabolism in macrophages contributes to breast cancer metastasis C_LI