Abstract

During metastatic dissemination, tumor cells come into contact with a wide variety of stromal cells in the microenvironment. In melanoma, primary tumors are in direct contact with keratinocytes, but as they progress and then metastasize, they then come into contact with subcutaneous tissues. Although this tissue is largely composed of adipocytes, little is known of the interaction between melanoma cells and adipocytes. Here, we demonstrate that adipocytes in the melanoma microenvironment are a key mediator of melanoma progression. Using a zebrafish model of melanoma, we find that melanoma cells home to adipocyte-rich areas in 57% of cases. Once in contact, the melanoma cells induce lipolysis in the adjacent adipocytes, resulting in the release of fatty acids into the extracellular environment. In turn, the melanoma cells take up these fatty acids through FATP proteins, long chain fatty acid transporters that are aberrantly expressed in ~40% of melanomas. Once inside the melanoma cell, these adipocyte derived lipids cause increases in tumor cell proliferation, invasion and metastasis. Global lipiodomic analysis revealed a core set of fatty acids that are increased in the melanoma cell after exposure to adipocytes. One fate of these lipids is utilization in the β-oxidation pathway to synthesize ATP for energy. However, surprisingly, we found that the acetyl CoA produced via β-oxidation can also be shunted and used for acetylation of histones, leading to global changes in H3K9 and H3K27Ac, along with widespread alterations of transcriptional programs in the melanoma cells. Taken together, our data demonstrate a mechanism by which adipocytes promote tumor progression by providing lipids that can alter the epigenetic state of the nearby cancer cells.