Department of Pathology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, United States.
Department of Bioinformatics and Biostatistics, University of Louisville, Louisville, United States.
Elife. 2024 Nov 8;13:RP101221. doi: 10.7554/eLife.101221.
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 murine macrophages. Specifically, unsaturated FAs, including linoleic acids (LA), activate the FABP4/CEBPα pathway, leading to triglyceride synthesis and lipid droplet formation. Furthermore, FABP4 enhances lipolysis and FA utilization by breast cancer cell lines, which promotes cancer cell migration in vitro and metastasis in vivo. Notably, a deficiency of FABP4 in murine 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.
肿瘤相关巨噬细胞（TAMs）的高密度与乳腺癌患者的预后和生存不良相关。最近的研究表明，TAMs 中的脂质积累可以促进各种模型中的肿瘤生长和转移。然而，驱动 TAMs 中脂质积累和肿瘤进展的确切分子机制在很大程度上仍然未知。在此，我们证明了与饱和脂肪酸（FAs）不同，不饱和脂肪酸（FAs）更有可能在鼠巨噬细胞中形成脂质滴。具体而言，不饱和 FAs，包括亚油酸（LA），激活 FABP4/CEBPα 通路，导致甘油三酯合成和脂质滴形成。此外，FABP4 增强了乳腺癌细胞系的脂肪分解和 FA 利用，从而促进了体外癌细胞迁移和体内转移。值得注意的是，鼠巨噬细胞中 FABP4 的缺乏显著减少了 LA 诱导的脂质代谢。因此，我们的研究结果表明 FABP4 作为一种关键的脂质信使，促进了 TAMs 中不饱和 FA 介导的脂质积累和脂肪分解，从而促进了乳腺癌的转移。
