Deregulation of PPARβ/δ target genes in tumor-associated macrophages by fatty acid ligands in the ovarian cancer microenvironment

// Tim Schumann 1,* , Till Adhikary 1,* , Annika Wortmann 1,* , Florian Finkernagel 1 , Sonja Lieber 1 , Evelyn Schnitzer 1 , Nathalie Legrand 1 , Yvonne Schober 2 , W. Andreas Nockher 2 , Philipp M. Toth 3 , Wibke E. Diederich 3 , Andrea Nist 4 , Thorsten Stiewe 4 , Uwe Wagner 5 , Silke Reinartz 5 , Sabine Müller-Brüsselbach 1 and Rolf Müller 1 1 Institute of Molecular Biology and Tumor Research (IMT), Philipps University, Marburg, Germany 2 Metabolomics Core Facility and Institute of Laboratory Medicine and Pathobiochemistry, Philipps University, Marburg, Germany 3 Medicinal Chemistry Core Facility and Institute of Pharmaceutical Chemistry, Philipps University, Marburg, Germany 4 Genomics Core Facility, Philipps University, Marburg, Germany 5 Clinic for Gynecology, Gynecological Oncology and Gynecological Endocrinology, Center for Tumor Biology and Immunology (ZTI), Philipps University, Marburg, Germany * These authors have contributed equally to this work Correspondence to: Rolf Müller, email: // Keywords : PPARβ/δ, ANGPTL4, ovarian carcinoma, tumor-associated macrophages, linoleic acid Received : December 23, 2014 Accepted : March 29, 2015 Published : April 15, 2015 Abstract The nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) 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 PPARβ/δ-regulated transcriptome and cistrome for TAMs from ovarian carcinoma patients. Comparison with monocyte-derived macrophages shows that the vast majority of direct PPARβ/δ 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 PPARβ/δ 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 PPARβ/δ agonists in macrophages. These fatty acid ligands accumulate in lipid droplets in TAMs, thereby providing a reservoir of PPARβ/δ ligands. These observations suggest that the deregulation of PPARβ/δ 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.