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

Pieter Goossens; Juan Rodriguez-Vita; Anders Etzerodt; Marion Masse; Olivia Rastoin; Victoire Gouirand; Thomas Ulas; Olympia Papantonopoulou; Miranda Van Eck; Nathalie Auphan-Anezin; Magali Bebien; Christophe Verthuy; Thien Phong Vu Manh; Martin Turner; Marc Dalod; Joachim L Schultze; Toby Lawrence

doi:10.1016/j.cmet.2019.02.016

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

Pieter Goossens, Juan Rodriguez-Vita, Anders Etzerodt, Marion Masse, Olivia Rastoin, Victoire Gouirand, Thomas Ulas, Olympia Papantonopoulou, Miranda Van Eck, Nathalie Auphan-Anezin, Magali Bebien, Christophe Verthuy, Thien Phong Vu Manh, Martin Turner, Marc Dalod, Joachim L Schultze, Toby Lawrence

Institut for Biomedicin - Forskning og uddannelse, Syd

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

341 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Cell Metabolism
Vol/bind	29
Nummer	6
Sider (fra-til)	1376-1389.e4
Antal sider	18
ISSN	1550-4131
DOI	https://doi.org/10.1016/j.cmet.2019.02.016
Status	Udgivet - 4 jun. 2019

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10.1016/j.cmet.2019.02.016

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Role of macrophages in tumor development
Etzerodt, A. (PI)
01/09/2014 → …
Projekter: Projekt › Forskning

Citationsformater

Goossens, P., Rodriguez-Vita, J., Etzerodt, A., Masse, M., Rastoin, O., Gouirand, V., Ulas, T., Papantonopoulou, O., Van Eck, M., Auphan-Anezin, N., Bebien, M., Verthuy, C., Vu Manh, T. P., Turner, M., Dalod, M., Schultze, J. L., & Lawrence, T. (2019). Membrane Cholesterol Efflux Drives Tumor-Associated Macrophage Reprogramming and Tumor Progression. Cell Metabolism, 29(6), 1376-1389.e4. https://doi.org/10.1016/j.cmet.2019.02.016

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title = "Membrane Cholesterol Efflux Drives Tumor-Associated Macrophage Reprogramming and Tumor Progression",

abstract = "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.",

keywords = "IL-4 signaling, cholesterol efflux, lipid rafts, ovarian cancer, tumor-associated macrophages",

author = "Pieter Goossens and Juan Rodriguez-Vita and Anders Etzerodt and Marion Masse and Olivia Rastoin and Victoire Gouirand and Thomas Ulas and Olympia Papantonopoulou and {Van Eck}, Miranda and Nathalie Auphan-Anezin and Magali Bebien and Christophe Verthuy and {Vu Manh}, {Thien Phong} and Martin Turner and Marc Dalod and Schultze, {Joachim L} and Toby Lawrence",

year = "2019",

month = jun,

day = "4",

doi = "10.1016/j.cmet.2019.02.016",

language = "English",

volume = "29",

pages = "1376--1389.e4",

journal = "Cell Metabolism",

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number = "6",

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Goossens, P, Rodriguez-Vita, J, Etzerodt, A, Masse, M, Rastoin, O, Gouirand, V, Ulas, T, Papantonopoulou, O, Van Eck, M, Auphan-Anezin, N, Bebien, M, Verthuy, C, Vu Manh, TP, Turner, M, Dalod, M, Schultze, JL & Lawrence, T 2019, 'Membrane Cholesterol Efflux Drives Tumor-Associated Macrophage Reprogramming and Tumor Progression', Cell Metabolism, bind 29, nr. 6, s. 1376-1389.e4. https://doi.org/10.1016/j.cmet.2019.02.016

TY - JOUR

T1 - Membrane Cholesterol Efflux Drives Tumor-Associated Macrophage Reprogramming and Tumor Progression

AU - Goossens, Pieter

AU - Rodriguez-Vita, Juan

AU - Etzerodt, Anders

AU - Masse, Marion

AU - Rastoin, Olivia

AU - Gouirand, Victoire

AU - Ulas, Thomas

AU - Papantonopoulou, Olympia

AU - Van Eck, Miranda

AU - Auphan-Anezin, Nathalie

AU - Bebien, Magali

AU - Verthuy, Christophe

AU - Vu Manh, Thien Phong

AU - Turner, Martin

AU - Dalod, Marc

AU - Schultze, Joachim L

AU - Lawrence, Toby

PY - 2019/6/4

Y1 - 2019/6/4

N2 - 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.

AB - 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.

KW - IL-4 signaling

KW - cholesterol efflux

KW - lipid rafts

KW - ovarian cancer

KW - tumor-associated macrophages

U2 - 10.1016/j.cmet.2019.02.016

DO - 10.1016/j.cmet.2019.02.016

M3 - Journal article

C2 - 30930171

SN - 1550-4131

VL - 29

SP - 1376-1389.e4

JO - Cell Metabolism

JF - Cell Metabolism

IS - 6

ER -

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

Abstract

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Role of macrophages in tumor development

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