title: Deregulation of PPARβ/δ target genes in tumor-associated macrophages by fatty acid ligands in the ovarian cancer microenvironment.
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.
authors.affiliation: Institute of Molecular Biology and Tumor Research (IMT), Philipps University, Marburg, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Schumann
authors.affiliation: Institute of Molecular Biology and Tumor Research (IMT), Philipps University, Marburg, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Adhikary
authors.affiliation: Institute of Molecular Biology and Tumor Research (IMT), Philipps University, Marburg, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Wortmann
authors.affiliation: Institute of Molecular Biology and Tumor Research (IMT), Philipps University, Marburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Finkernagel
authors.affiliation: Institute of Molecular Biology and Tumor Research (IMT), Philipps University, Marburg, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Lieber
authors.affiliation: Institute of Molecular Biology and Tumor Research (IMT), Philipps University, Marburg, Germany.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Schnitzer
authors.affiliation: Institute of Molecular Biology and Tumor Research (IMT), Philipps University, Marburg, Germany.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Legrand
authors.affiliation: Metabolomics Core Facility and Institute of Laboratory Medicine and Pathobiochemistry, Philipps University, Marburg, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Schober
authors.affiliation: Metabolomics Core Facility and Institute of Laboratory Medicine and Pathobiochemistry, Philipps University, Marburg, Germany.
authors.forename: W Andreas
authors.initials: WA
authors.lastname: Nockher
authors.affiliation: Medicinal Chemistry Core Facility and Institute of Pharmaceutical Chemistry, Philipps University, Marburg, Germany.
authors.forename: Philipp M
authors.initials: PM
authors.lastname: Toth
authors.affiliation: Medicinal Chemistry Core Facility and Institute of Pharmaceutical Chemistry, Philipps University, Marburg, Germany.
authors.forename: Wibke E
authors.initials: WE
authors.lastname: Diederich
authors.affiliation: Genomics Core Facility, Philipps University, Marburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Nist
authors.affiliation: Genomics Core Facility, Philipps University, Marburg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Stiewe
authors.affiliation: Clinic for Gynecology, Gynecological Oncology and Gynecological Endocrinology, Center for Tumor Biology and Immunology (ZTI), Philipps University, Marburg, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Wagner
authors.affiliation: Clinic for Gynecology, Gynecological Oncology and Gynecological Endocrinology, Center for Tumor Biology and Immunology (ZTI), Philipps University, Marburg, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Reinartz
authors.affiliation: Institute of Molecular Biology and Tumor Research (IMT), Philipps University, Marburg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Müller-Brüsselbach
authors.affiliation: Institute of Molecular Biology and Tumor Research (IMT), Philipps University, Marburg, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D005227:Fatty Acids; D005260:Female; D006801:Humans; D008024:Ligands; D019787:Linoleic Acid / Q000097:blood / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000235:genetics; D010051:Ovarian Neoplasms / Q000097:blood* / Q000235:genetics*; D047494:PPAR delta / Q000097:blood / Q000235:genetics*; D048068:PPAR-beta / Q000097:blood / Q000235:genetics*; D059016:Tumor Microenvironment / Q000235:genetics*
chemical_list: D005227:Fatty Acids; D008024:Ligands; D047494:PPAR delta; D048068:PPAR-beta; D019787:Linoleic Acid
keywords: ANGPTL4; PPARβ/δ; linoleic acid; ovarian carcinoma; tumor-associated macrophages