Stromal lipid species dictate melanoma metastasis and tropism [MeWo_RNA_seq]
Cancer cells adapt to signals in the tumor microenvironment (TME), but the TME cues that impact metastasis and tropism are unknown. We show that stromal lipids from young adipocytes are taken up by melanoma cells, and lipids increase melanoma oxidative phosphorylation (OXPHOS) and oxidative stress, which decreases metastatic burden. In contrast, the aged TME provides fewer lipids, leading to lower OXPHOS and higher metastatic capacity. Young adipocytes transfer phosphatidylcholine (PC) to melanoma cells, where PC upregulates PI3K/AKT and mitochondrial OXPHOS. Melanoma cells with high OXPHOS predominantly seed the lung and brain, but do not colonise the liver, and decreasing oxidative stress with antioxidant supplements shifts tropism from the lung to the liver. In contrast, although the aged stroma has fewer total lipids, it has more ceramides, which activate the S1P/STAT3/IL6 signalling axis to direct melanoma liver tropism. Inhibiting OXPHOS in the young stroma and blocking IL6 receptor in the aged stroma reduces the age-specific patterns of metastasis imposed by stromal lipids. Overall design: RNA sequencing of MeWo cells exposed to serum free (control), old adipocytes secretome (OA) and young adipocyte secretome (YA). All treated for 24 hours.