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

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-regulate...

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Autores principales: Schumann, Tim, Adhikary, Till, Wortmann, Annika, Finkernagel, Florian, Lieber, Sonja, Schnitzer, Evelyn, Legrand, Nathalie, Schober, Yvonne, Nockher, W. Andreas, Toth, Philipp M., Diederich, Wibke E., Nist, Andrea, Stiewe, Thorsten, Wagner, Uwe, Reinartz, Silke, Müller-Brüsselbach, Sabine, Müller, Rolf
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537024/
https://www.ncbi.nlm.nih.gov/pubmed/25968567
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author Schumann, Tim
Adhikary, Till
Wortmann, Annika
Finkernagel, Florian
Lieber, Sonja
Schnitzer, Evelyn
Legrand, Nathalie
Schober, Yvonne
Nockher, W. Andreas
Toth, Philipp M.
Diederich, Wibke E.
Nist, Andrea
Stiewe, Thorsten
Wagner, Uwe
Reinartz, Silke
Müller-Brüsselbach, Sabine
Müller, Rolf
author_facet Schumann, Tim
Adhikary, Till
Wortmann, Annika
Finkernagel, Florian
Lieber, Sonja
Schnitzer, Evelyn
Legrand, Nathalie
Schober, Yvonne
Nockher, W. Andreas
Toth, Philipp M.
Diederich, Wibke E.
Nist, Andrea
Stiewe, Thorsten
Wagner, Uwe
Reinartz, Silke
Müller-Brüsselbach, Sabine
Müller, Rolf
author_sort Schumann, Tim
collection PubMed
description 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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spelling pubmed-45370242015-08-26 Deregulation of PPARβ/δ target genes in tumor-associated macrophages by fatty acid ligands in the ovarian cancer microenvironment Schumann, Tim Adhikary, Till Wortmann, Annika Finkernagel, Florian Lieber, Sonja Schnitzer, Evelyn Legrand, Nathalie Schober, Yvonne Nockher, W. Andreas Toth, Philipp M. Diederich, Wibke E. Nist, Andrea Stiewe, Thorsten Wagner, Uwe Reinartz, Silke Müller-Brüsselbach, Sabine Müller, Rolf Oncotarget Research Paper 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. Impact Journals LLC 2015-04-15 /pmc/articles/PMC4537024/ /pubmed/25968567 Text en Copyright: © 2015 Schumann et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Schumann, Tim
Adhikary, Till
Wortmann, Annika
Finkernagel, Florian
Lieber, Sonja
Schnitzer, Evelyn
Legrand, Nathalie
Schober, Yvonne
Nockher, W. Andreas
Toth, Philipp M.
Diederich, Wibke E.
Nist, Andrea
Stiewe, Thorsten
Wagner, Uwe
Reinartz, Silke
Müller-Brüsselbach, Sabine
Müller, Rolf
Deregulation of PPARβ/δ target genes in tumor-associated macrophages by fatty acid ligands in the ovarian cancer microenvironment
title Deregulation of PPARβ/δ target genes in tumor-associated macrophages by fatty acid ligands in the ovarian cancer microenvironment
title_full Deregulation of PPARβ/δ target genes in tumor-associated macrophages by fatty acid ligands in the ovarian cancer microenvironment
title_fullStr Deregulation of PPARβ/δ target genes in tumor-associated macrophages by fatty acid ligands in the ovarian cancer microenvironment
title_full_unstemmed Deregulation of PPARβ/δ target genes in tumor-associated macrophages by fatty acid ligands in the ovarian cancer microenvironment
title_short Deregulation of PPARβ/δ target genes in tumor-associated macrophages by fatty acid ligands in the ovarian cancer microenvironment
title_sort deregulation of pparβ/δ target genes in tumor-associated macrophages by fatty acid ligands in the ovarian cancer microenvironment
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537024/
https://www.ncbi.nlm.nih.gov/pubmed/25968567
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