Adipocyte-Derived Lipids Mediate Melanoma Progression via FATP Proteins

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 and 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 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. 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. .

Adipocyte extracellular vesicles carry enzymes and fatty acids that stimulate mitochondrial metabolism and remodeling in tumor cells

“…Cellular components in the tumor microenvironment are major regulators of tumor metabolism, driving cancer cells to favor certain metabolic pathways (Gouirand et al, 2018). Indeed, tumor secretions trigger lipolysis in neighboring adipocytes (Dirat et al, 2011), and the released FA fuel fatty acid oxidation (FAO) in tumors, which increases tumor aggressiveness (Nieman et al, 2011;Balaban et al, 2017;Wang et al, 2017;Zhang et al, 2018). Indeed, tumor secretions trigger lipolysis in neighboring adipocytes (Dirat et al, 2011), and the released FA fuel fatty acid oxidation (FAO) in tumors, which increases tumor aggressiveness (Nieman et al, 2011;Balaban et al, 2017;Wang et al, 2017;Zhang et al, 2018).…”

“…Adipocytes, the main component of AT, reside in many cancer microenvironments and contribute to tumor progression through soluble factors, such as leptin or interleukin 6, and extracellular matrix remodeling (Andarawewa et al, 2005;Dirat et al, 2011;Duong et al, 2017). Recent findings highlight a metabolic cooperation between adipocytes and tumor cells, which is proving to be a key process in their tumor-promoting effects (Nieman et al, 2011;Balaban et al, 2017;Wang et al, 2017;Zhang et al, 2018). Cellular components in the tumor microenvironment are major regulators of tumor metabolism, driving cancer cells to favor certain metabolic pathways (Gouirand et al, 2018).…”

“…In particular, adipocytes provide a local supply of fatty acids (FA) that can serve as an energy source for tumors. Indeed, tumor secretions trigger lipolysis in neighboring adipocytes (Dirat et al, 2011), and the released FA fuel fatty acid oxidation (FAO) in tumors, which increases tumor aggressiveness (Nieman et al, 2011;Balaban et al, 2017;Wang et al, 2017;Zhang et al, 2018). FAO has recently emerged as a pro-tumoral pathway involved in cancer cell proliferation, stemness, and invasion (Carracedo et al, 2013;Kuo & Ann, 2018), but many of the molecular mechanisms behind these effects remain elusive.…”

Multiple Myeloma and Fatty Acid Metabolism

“…Blask and colleagues found that increased FATPs enhance FA uptake in rat hepatomas . Zhang et al showed that melanoma cells express FATPs, and that these proteins mediate transport of FAs from subcutaneous adipocytes to the tumor cells, which utilize FAs to fuel their growth and proliferation . Interestingly, blocking FATP reduced melanoma growth and lipid content both in in vitro and in vivo studies .…”

“…Zhang et al showed that melanoma cells express FATPs, and that these proteins mediate transport of FAs from subcutaneous adipocytes to the tumor cells, which utilize FAs to fuel their growth and proliferation . Interestingly, blocking FATP reduced melanoma growth and lipid content both in in vitro and in vivo studies . However, as it is not clear yet how FATPs mediate FA uptake, and which FATPs have FA uptake and acyl‐CoA synthetase activity, more research into the roles of FATPs in cancer is needed.…”