Dysregulation of cholesterol homeostasis in human lung cancer tissue and tumour-associated macrophages. Hoppstädter, J., Dembek, A., Höring, M., Schymik, H. S., Dahlem, C., Sultan, A., Wirth, N., Al-Fityan, S., Diesel, B., Gasparoni, G., Walter, J., Helms, V., Huwer, H., Simon, M., Liebisch, G., Schulz, M. H., & Kiemer, A. K. EBioMedicine, 72:103578, October, 2021.
doi  abstract   bibtex   
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. FUNDING: Deutsche Forschungsgemeinschaft (DFG), Landesforschungsf €orderungsprogramm Saarland (LFPP).
@article{hoppstadter_dysregulation_2021,
	title = {Dysregulation of cholesterol homeostasis in human lung cancer tissue and tumour-associated macrophages},
	volume = {72},
	issn = {2352-3964},
	doi = {10.1016/j.ebiom.2021.103578},
	abstract = {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.
FUNDING: Deutsche Forschungsgemeinschaft (DFG), Landesforschungsf €orderungsprogramm Saarland (LFPP).},
	language = {eng},
	journal = {EBioMedicine},
	author = {Hoppstädter, Jessica and Dembek, Anna and Höring, Marcus and Schymik, Hanna S. and Dahlem, Charlotte and Sultan, Afnan and Wirth, Natalie and Al-Fityan, Salma and Diesel, Britta and Gasparoni, Gilles and Walter, Jörn and Helms, Volkhard and Huwer, Hanno and Simon, Martin and Liebisch, Gerhard and Schulz, Marcel H. and Kiemer, Alexandra K.},
	month = oct,
	year = {2021},
	pmid = {34571364},
	pmcid = {PMC8479395},
	keywords = {ABCA1, ABCG1, Adenocarcinoma, ATR-101, Cell Line, Tumor, Cholesterol, Gene Expression, Homeostasis, Humans, innate immune response, Lung Neoplasms, Non-small cell lung cancer, Tumor Microenvironment, Tumor-Associated Macrophages},
	pages = {103578},
	file = {Volltext:/Users/mschulz/Zotero/storage/5IQGPBTG/Hoppstädter et al. - 2021 - Dysregulation of cholesterol homeostasis in human .pdf:application/pdf},
}
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