Journal
CELL METABOLISM
Volume 29, Issue 6, Pages 1376-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2019.02.016
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Funding
- L'Agence Nationale de la Recherche (ANR) [ANR-09-MIEN-029-01, ANR-10-BLAN-1302-01]
- European Research Council [260753]
- INSERM, CNRS
- Aix-Marseille-Universite
- Marie Curie actions IEF [234823]
- French Ligue Nationale contre le Cancer (LNCC)
- Novo Nordisk Foundation [NNF14OC0008781]
- France Bio Imaging [ANR-10-INBS-04-01]
- People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme FP7/2077-2013 under REA grant [317445]
- BBSRC [BB/I01246X/1, BBS/E/B/000C0428, BB/M021343/1] Funding Source: UKRI
- European Research Council (ERC) [260753] Funding Source: European Research Council (ERC)
- Agence Nationale de la Recherche (ANR) [ANR-10-BLAN-1302] Funding Source: Agence Nationale de la Recherche (ANR)
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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 IFN gamma-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.
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