Adipocyte-Derived Lipids Mediate Melanoma Progression via FATP Proteins

作者：Zhang, Maomao; Di Martino, Julie S.; Bowman, Robert L.; Campbell, Nathaniel R.; Baksh, Sanjeethan C.; Simon-Vermot, Theresa; Kim, Isabella S.; Haldeman, Pearce; Mondal, Chandrani; Yong-Gonzales, Vladimir; Abu-Akeel, Mohsen; Merghoub, Taha; Jones, Drew R.; Zhu, Xiphias Ge; Arora, Arshi; Ariyan, Charlotte E.; Birsoy, Kivanc; Wolchok, Jedd D.; Panageas, Katherine S.; Hollmann, Travis; Bravo-Cordero, Jose Javier; White, Richard M.^*

来源：Cancer Discovery, 2018, 8(8): 1006-1025.

DOI：10.1158/2159-8290.CD-17-1371

• NONMELANOMA SKIN-CANCER
• ACID TRANSPORT PROTEINS
• BODY-MASS INDEX
• IN-VIVO
• METASTATIC MELANOMA
• MALIGNANT-MELANOMA
• TUMOR PROGRESSION
• TARGETED THERAPY
• OBESITY
• GROWTH

Advanced, metastatic melanomas frequently grow in subcutaneous tissues and portend a poor prognosis. Though subcutaneous tissues are largely composed of adipocytes, the mechanisms by which adipocytes influence melanoma are poorly understood. Using in vitro and in vivo models, we find that adipocytes increase proliferation and invasion of adjacent melanoma cells. Additionally, adipocytes directly transfer lipids to melanoma cells, which alters tumor cell metabolism. Adipocyte-derived lipids are transferred to melanoma cells through the FATP/SLC27A family of lipid transporters expressed on the tumor cell surface. Among the six FATP/SLC27A family members, melanomas significantly overexpress FATP1/SLC27A1. Melanocyte-specific FATP1 expression cooperates with BRAF(V600E) in transgenic zebrafish to accelerate melanoma development, an effect that is similarly seen in mouse xenograft studies. Pharmacologic blockade of FATPs with the small-molecule inhibitor Lipofermata abrogates lipid transport into melanoma cells and reduces melanoma growth and invasion. These data demonstrate that stromal adipocytes can drive melanoma progression through FATP lipid transporters and represent a new target aimed at interrupting adipocyte-melanoma cross-talk. @@@ SIGNIFICANCE: We demonstrate that stromal adipocytes are donors of lipids that mediate melanoma progression. Adipocyte-derived lipids are taken up by FATP proteins that are aberrantly expressed in melanoma. Inhibition of FATPs decreases melanoma lipid uptake, invasion, and growth. We provide a mechanism for how stromal adipocytes drive tumor progression and demonstrate a novel microenvironmental therapeutic target.

• 出版日期2018-8