title: Transcriptional and metabolic reprogramming induce an inflammatory phenotype in non-medullary thyroid carcinoma-induced macrophages.
abstract: Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment in non-medullary thyroid cancer (TC), the most common endocrine malignancy. However, little is known regarding the regulation of their function in TC. Transcriptome analysis in a model of TC-induced macrophages identified increased inflammatory characteristics and rewiring of cell metabolism as key functional changes. This functional reprogramming was partly mediated by TC-derived lactate that induced upregulation of cytokine production through an AKT1/mTOR-dependent increase in aerobic glycolysis. This led to epigenetic modifications at the level of histone methylation, and subsequently long-term functional changes. Immunohistochemistry assessment validated the increase in glycolysis enzymes and lactate receptor in TAMs in tissue samples from patients with TC. In conclusion, Akt/mTOR-dependent glycolysis mediates TC-induced reprogramming of TAMs and inflammation, and this may represent a novel therapeutic target in TC.
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center , Nijmegen, the Netherlands.
authors.forename: Rob J W
authors.identifier: 0000-0002-6649-7190
authors.initials: RJ
authors.lastname: Arts
authors.affiliation: Department of Pathology, Radboud University Medical Center , Nijmegen, the Netherlands.
authors.forename: Theo S
authors.identifier: 0000-0003-4990-6084
authors.initials: TS
authors.lastname: Plantinga
authors.affiliation: Genomics and Immunoregulation, LIMES-Institute, University of Bonn , Bonn, Germany.
authors.forename: Sander
authors.identifier: 0000-0003-2599-1202
authors.initials: S
authors.lastname: Tuit
authors.affiliation: Genomics and Immunoregulation, LIMES-Institute, University of Bonn , Bonn, Germany.
authors.forename: Thomas
authors.identifier: 0000-0002-9785-4197
authors.initials: T
authors.lastname: Ulas
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center , Nijmegen, the Netherlands.
authors.forename: Bas
authors.initials: B
authors.lastname: Heinhuis
authors.affiliation: Department of Pathology, Radboud University Medical Center , Nijmegen, the Netherlands.
authors.forename: Marika
authors.initials: M
authors.lastname: Tesselaar
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center , Nijmegen, the Netherlands.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Sloot
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen, the Netherlands.
authors.forename: Gosse J
authors.identifier: 0000-0002-6750-1665
authors.initials: GJ
authors.lastname: Adema
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center , Nijmegen, the Netherlands.
authors.forename: Leo A B
authors.identifier: 0000-0001-6166-9830
authors.initials: LA
authors.lastname: Joosten
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center , Nijmegen, the Netherlands.
authors.forename: Johannes W A
authors.initials: JW
authors.lastname: Smit
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center , Nijmegen, the Netherlands.
authors.forename: Mihai G
authors.identifier: 0000-0003-2421-6052
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Genomics and Immunoregulation, LIMES-Institute, University of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases, Bonn, Germany.
authors.forename: Joachim L
authors.identifier: 0000-0003-2812-9853
authors.initials: JL
authors.lastname: Schultze
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center , Nijmegen, the Netherlands.
authors.forename: Romana T
authors.identifier: 0000-0002-9603-0460
authors.initials: RT
authors.lastname: Netea-Maier
keywords: Cytokines; epigenetics; immunometabolism; lactate; thyroid cancer; tumor-associated macrophages