Deregulation of PPARβ/δ target genes in tumor-associated macrophages by fatty acid ligands in the ovarian cancer microenvironment
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Tim Schumann1,*, Till Adhikary1,*, Annika Wortmann1,*, Florian Finkernagel1, Sonja Lieber1, Evelyn Schnitzer1, Nathalie Legrand1, Yvonne Schober2, W. Andreas Nockher2, Philipp M. Toth3, Wibke E. Diederich3, Andrea Nist4, Thorsten Stiewe4, Uwe Wagner5, Silke Reinartz5, Sabine Müller-Brüsselbach1 and Rolf Müller1
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
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
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.
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