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Cancer Discov. 2018 Aug;8(8):1006-1025. doi: 10.1158/2159-8290.CD-17-1371. Epub 2018 Jun 14.

Adipocyte-Derived Lipids Mediate Melanoma Progression via FATP Proteins.

Author information

1
Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York.
2
Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine, Tisch Cancer Institute at Mount Sinai, New York, New York.
3
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
4
Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, New York.
5
Department of Computational and Systems Biology, Memorial Sloan Kettering Cancer Center, New York, New York.
6
Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, New York.
7
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
8
Metabolomics Core Resource Library, New York University Langone Health, New York, New York.
9
Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, New York.
10
Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
11
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
12
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
13
Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York. whiter@mskcc.org.

Abstract

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 BRAFV600E 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. Cancer Discov; 8(8); 1006-25. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 899.

PMID:
29903879
PMCID:
PMC6192670
[Available on 2019-08-01]
DOI:
10.1158/2159-8290.CD-17-1371

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