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Membrane Cholesterol Efflux Drives Tumor-Associated Macrophage Reprogramming and Tumor Progression

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  • Pieter Goossens, CNRS, Aix Marseille University, INSERM, CIML, Marseille 13009, France; Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, 6229HX Maastricht, the Netherlands.
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  • Juan Rodriguez-Vita, CNRS, Aix Marseille University, INSERM, CIML, Marseille 13009, France; Vascular Signaling and Cancer (A270), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
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  • Anders Etzerodt
  • Marion Masse, CNRS, Aix Marseille University, INSERM, CIML, Marseille 13009, France.
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  • Olivia Rastoin, CNRS, Aix Marseille University, INSERM, CIML, Marseille 13009, France.
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  • Victoire Gouirand, CNRS, Aix Marseille University, INSERM, CIML, Marseille 13009, France.
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  • Thomas Ulas, Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn 53115, Germany; PRECISE Platform for Single Cell Genomics and Epigenomics, German Center for Neurodegenerative Diseases and University of Bonn, Bonn 53127, Germany.
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  • Olympia Papantonopoulou, Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn 53115, Germany.
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  • Miranda Van Eck, Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Universiteit Leiden, 2300 Leiden, the Netherlands.
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  • Nathalie Auphan-Anezin, CNRS, Aix Marseille University, INSERM, CIML, Marseille 13009, France.
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  • Magali Bebien, CNRS, Aix Marseille University, INSERM, CIML, Marseille 13009, France.
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  • Christophe Verthuy, CNRS, Aix Marseille University, INSERM, CIML, Marseille 13009, France.
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  • Thien Phong Vu Manh, CNRS, Aix Marseille University, INSERM, CIML, Marseille 13009, France.
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  • Martin Turner, Laboratory of Lymphocyte Signaling and Development, The Babraham Institute, Cambridge CB22 3AT, UK.
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  • Marc Dalod, CNRS, Aix Marseille University, INSERM, CIML, Marseille 13009, France.
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  • Joachim L Schultze, Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn 53115, Germany; PRECISE Platform for Single Cell Genomics and Epigenomics, German Center for Neurodegenerative Diseases and University of Bonn, Bonn 53127, Germany.
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  • Toby Lawrence, CNRS, Aix Marseille University, INSERM, CIML, Marseille 13009, France; Centre for Inflammation Biology and Cancer Immunology, School of Immunology & Micriboal Sciences, King's College London, London SE1 1UL, UK; Henan Key Laboratory of Immunology and Targeted Therapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang 453003, Henan Province, China. Electronic address: toby.lawrence@kcl.ac.uk.

Macrophages possess intrinsic tumoricidal activity, yet tumor-associated macrophages (TAMs) rapidly adopt an alternative phenotype within the tumor microenvironment that is marked by tumor-promoting immunosuppressive and trophic functions. The mechanisms that promote such TAM polarization remain poorly understood, but once identified, they may represent important therapeutic targets to block the tumor-promoting functions of TAMs and restore their anti-tumor potential. Here, we have characterized TAMs in a mouse model of metastatic ovarian cancer. We show that ovarian cancer cells promote membrane-cholesterol efflux and depletion of lipid rafts from macrophages. Increased cholesterol efflux promoted IL-4-mediated reprogramming, including inhibition of IFNγ-induced gene expression. Genetic deletion of ABC transporters, which mediate cholesterol efflux, reverts the tumor-promoting functions of TAMs and reduces tumor progression. These studies reveal an unexpected role for membrane-cholesterol efflux in driving TAM-mediated tumor progression while pointing to a potentially novel anti-tumor therapeutic strategy.

Original languageEnglish
JournalCell Metabolism
Volume29
Issue6
Pages (from-to)1376-1389.e4
Number of pages18
ISSN1550-4131
DOIs
Publication statusPublished - 4 Jun 2019

    Research areas

  • IL-4 signaling, cholesterol efflux, lipid rafts, ovarian cancer, tumor-associated macrophages

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