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 - Thien Phong Vu Manh, null
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 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.
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 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.
KW - TISSUE MACROPHAGES
KW - MYELOID CELLS
KW - HYALURONAN
KW - EXPRESSION
KW - MONOCYTES
KW - PI3K-GAMMA
U2 - 10.1016/j.cmet.2019.02.016
DO - 10.1016/j.cmet.2019.02.016
M3 - Article
VL - 29
SP - 1376
EP - 1389
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 6
ER -