Oncotarget

Research Papers:

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

Tim Schumann, Till Adhikary, Annika Wortmann, Florian Finkernagel, Sonja Lieber, Evelyn Schnitzer, Nathalie Legrand, Yvonne Schober, W. Andreas Nockher, Philipp M. Toth, Wibke E. Diederich, Andrea Nist, Thorsten Stiewe, Uwe Wagner, Silke Reinartz, Sabine Müller-Brüsselbach and Rolf Müller _

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Oncotarget. 2015; 6:13416-13433. https://doi.org/10.18632/oncotarget.3826

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Abstract

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

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.


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