Deregulation of PPAR?/? target genes in tumor-associated macrophages by fatty acid ligands in the ovarian cancer microenvironment.

ABSTRACT: The nuclear receptor peroxisome proliferator-activated receptor ?/? (PPAR?/?) is a lipid ligand-inducible transcription factor associated with macrophage polarization. However, its function in tumor-associated macrophages (TAMs) has not been investigated to date. Here, we report the PPAR?/?-regulated transcriptome and cistrome for TAMs from ovarian carcinoma patients. Comparison with monocyte-derived macrophages shows that the vast majority of direct PPAR?/? target genes are upregulated in TAMs and largely refractory to synthetic agonists, but repressible by inverse agonists. Besides genes with metabolic functions, these include cell type-selective genes associated with immune regulation and tumor progression, e.g., LRP5, CD300A, MAP3K8 and ANGPTL4. This deregulation is not due to increased expression of PPAR?/? or its enhanced recruitment to target genes. Instead, lipidomic analysis of malignancy-associated ascites revealed high concentrations of polyunsaturated fatty acids, in particular linoleic acid, acting as potent PPAR?/? agonists in macrophages. These fatty acid ligands accumulate in lipid droplets in TAMs, thereby providing a reservoir of PPAR?/? ligands. These observations suggest that the deregulation of PPAR?/? target genes by ligands of the tumor microenvironment contributes to the pro-tumorigenic polarization of ovarian carcinoma TAMs. This conclusion is supported by the association of high ANGPTL4 expression with a shorter relapse-free survival in serous ovarian carcinoma.

SUBMITTER: Schumann T 

PROVIDER: S-EPMC4537024 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature