Cell Metabolism
Volume 29, Issue 6, 4 June 2019, Pages 1376-1389.e4
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Article
Membrane Cholesterol Efflux Drives Tumor-Associated Macrophage Reprogramming and Tumor Progression

https://doi.org/10.1016/j.cmet.2019.02.016Get rights and content
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Highlights

  • Ovarian cancer cells promote membrane-cholesterol efflux in TAMs

  • Cholesterol efflux depletes lipid rafts and increases IL-4 signaling in TAMs

  • Genetic deletion of ABC transporters reverts the tumor-promoting functions of TAMs

Summary

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

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

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11

These authors contributed equally

12

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