Dysregulation of cholesterol homeostasis in human lung cancer tissue and tumour-associated macrophages
Background: Based on reports on elevated cholesterol levels in cancer cells, strategies to lower cholesterol synthesis have been suggested as an antitumour strategy. However, cholesterol depletion has also been shown to induce tumour-promoting actions in tumour-associated macrophages (TAMs). Methods...
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2021-10-01
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doaj-3207fcd633e64b2fbbeaa98ad6fb11a72021-09-27T04:26:53ZengElsevierEBioMedicine2352-39642021-10-0172103578Dysregulation of cholesterol homeostasis in human lung cancer tissue and tumour-associated macrophagesJessica Hoppstädter0Anna Dembek1Marcus Höring2Hanna S. Schymik3Charlotte Dahlem4Afnan Sultan5Natalie Wirth6Salma Al-Fityan7Britta Diesel8Gilles Gasparoni9Jörn Walter10Volkhard Helms11Hanno Huwer12Martin Simon13Gerhard Liebisch14Marcel H. Schulz15Alexandra K. Kiemer16Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, GermanyDepartment of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, GermanyInstitute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, GermanyDepartment of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, GermanyDepartment of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, GermanyCenter for Bioinformatics, Saarland University, Saarbrücken, GermanyCenter for Bioinformatics, Saarland University, Saarbrücken, GermanyDepartment of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, GermanyDepartment of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, GermanyDepartment of Genetics/Epigenetics, Saarland University, Saarbrücken, GermanyDepartment of Genetics/Epigenetics, Saarland University, Saarbrücken, GermanyCenter for Bioinformatics, Saarland University, Saarbrücken, GermanyDepartment of Cardiothoracic Surgery, Völklingen Heart Center, Völklingen, GermanyMolecular Cell Biology and Microbiology, University of Wuppertal, Faculty of Mathematics and Natural Sciences, Wuppertal, GermanyInstitute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, GermanyInstitute for Cardiovascular Regeneration, Goethe University, Frankfurt am Main, GermanyDepartment of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, Germany; Corresponding author at: Pharmaceutical Biology, Saarland University, D-66123 Saarbrücken, Germany.Background: Based on reports on elevated cholesterol levels in cancer cells, strategies to lower cholesterol synthesis have been suggested as an antitumour strategy. However, cholesterol depletion has also been shown to induce tumour-promoting actions in tumour-associated macrophages (TAMs). Methods: We performed lipidomic and transcriptomic analyses of human lung cancer material. To assess whether the TAM phenotype is shaped by secreted factors produced by tumour cells, primary human monocyte-derived macrophages were polarized towards a TAM-like phenotype using tumour cell-conditioned medium. Findings: Lipidomic analysis of lung adenocarcinoma (n=29) and adjacent non-tumour tissues (n=22) revealed a significant accumulation of free cholesterol and cholesteryl esters within the tumour tissue. In contrast, cholesterol levels were reduced in TAMs isolated from lung adenocarcinoma tissues when compared with alveolar macrophages (AMs) obtained from adjacent non-tumour tissues. Bulk-RNA-Seq revealed that genes involved in cholesterol biosynthesis and metabolism were downregulated in TAMs, while cholesterol efflux transporters were upregulated. In vitro polarized TAM-like macrophages showed an attenuated lipogenic gene expression signature and exhibited lower cholesterol levels compared with non-polarized macrophages. A genome-wide comparison by bulk RNA-Seq confirmed a high similarity of ex vivo TAMs and in vitro TAM-like macrophages. Modulation of intracellular cholesterol levels by either starving, cholesterol depletion, or efflux transporter inhibition indicated that cholesterol distinctly shapes macrophage gene expression. Interpretation: Our data show an opposite dysregulation of cholesterol homeostasis in tumour tissue vs. TAMs. Polarization of in vitro differentiated macrophages by tumour cell-conditioned medium recapitulates key features of ex vivo TAMs.http://www.sciencedirect.com/science/article/pii/S2352396421003716Non-small cell lung cancerinnate immune responseABCA1ABCG1ATR-101 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jessica Hoppstädter Anna Dembek Marcus Höring Hanna S. Schymik Charlotte Dahlem Afnan Sultan Natalie Wirth Salma Al-Fityan Britta Diesel Gilles Gasparoni Jörn Walter Volkhard Helms Hanno Huwer Martin Simon Gerhard Liebisch Marcel H. Schulz Alexandra K. Kiemer |
spellingShingle |
Jessica Hoppstädter Anna Dembek Marcus Höring Hanna S. Schymik Charlotte Dahlem Afnan Sultan Natalie Wirth Salma Al-Fityan Britta Diesel Gilles Gasparoni Jörn Walter Volkhard Helms Hanno Huwer Martin Simon Gerhard Liebisch Marcel H. Schulz Alexandra K. Kiemer Dysregulation of cholesterol homeostasis in human lung cancer tissue and tumour-associated macrophages EBioMedicine Non-small cell lung cancer innate immune response ABCA1 ABCG1 ATR-101 |
author_facet |
Jessica Hoppstädter Anna Dembek Marcus Höring Hanna S. Schymik Charlotte Dahlem Afnan Sultan Natalie Wirth Salma Al-Fityan Britta Diesel Gilles Gasparoni Jörn Walter Volkhard Helms Hanno Huwer Martin Simon Gerhard Liebisch Marcel H. Schulz Alexandra K. Kiemer |
author_sort |
Jessica Hoppstädter |
title |
Dysregulation of cholesterol homeostasis in human lung cancer tissue and tumour-associated macrophages |
title_short |
Dysregulation of cholesterol homeostasis in human lung cancer tissue and tumour-associated macrophages |
title_full |
Dysregulation of cholesterol homeostasis in human lung cancer tissue and tumour-associated macrophages |
title_fullStr |
Dysregulation of cholesterol homeostasis in human lung cancer tissue and tumour-associated macrophages |
title_full_unstemmed |
Dysregulation of cholesterol homeostasis in human lung cancer tissue and tumour-associated macrophages |
title_sort |
dysregulation of cholesterol homeostasis in human lung cancer tissue and tumour-associated macrophages |
publisher |
Elsevier |
series |
EBioMedicine |
issn |
2352-3964 |
publishDate |
2021-10-01 |
description |
Background: Based on reports on elevated cholesterol levels in cancer cells, strategies to lower cholesterol synthesis have been suggested as an antitumour strategy. However, cholesterol depletion has also been shown to induce tumour-promoting actions in tumour-associated macrophages (TAMs). Methods: We performed lipidomic and transcriptomic analyses of human lung cancer material. To assess whether the TAM phenotype is shaped by secreted factors produced by tumour cells, primary human monocyte-derived macrophages were polarized towards a TAM-like phenotype using tumour cell-conditioned medium. Findings: Lipidomic analysis of lung adenocarcinoma (n=29) and adjacent non-tumour tissues (n=22) revealed a significant accumulation of free cholesterol and cholesteryl esters within the tumour tissue. In contrast, cholesterol levels were reduced in TAMs isolated from lung adenocarcinoma tissues when compared with alveolar macrophages (AMs) obtained from adjacent non-tumour tissues. Bulk-RNA-Seq revealed that genes involved in cholesterol biosynthesis and metabolism were downregulated in TAMs, while cholesterol efflux transporters were upregulated. In vitro polarized TAM-like macrophages showed an attenuated lipogenic gene expression signature and exhibited lower cholesterol levels compared with non-polarized macrophages. A genome-wide comparison by bulk RNA-Seq confirmed a high similarity of ex vivo TAMs and in vitro TAM-like macrophages. Modulation of intracellular cholesterol levels by either starving, cholesterol depletion, or efflux transporter inhibition indicated that cholesterol distinctly shapes macrophage gene expression. Interpretation: Our data show an opposite dysregulation of cholesterol homeostasis in tumour tissue vs. TAMs. Polarization of in vitro differentiated macrophages by tumour cell-conditioned medium recapitulates key features of ex vivo TAMs. |
topic |
Non-small cell lung cancer innate immune response ABCA1 ABCG1 ATR-101 |
url |
http://www.sciencedirect.com/science/article/pii/S2352396421003716 |
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