Dietary palmitic acid promotes a prometastatic epigenetic memory related to tumor innervation [I]

Metastasis is promoted by fatty acid (FA) uptake and metabolism1-2. How this works, or whether all dietary FAs are prometastatic, is not known. Here we show that dietary palmitic acid (PA), but not oleic acid (OA) or linoleic acid, promotes metastasis, indicating specificity of action for distinct FAs. Strikingly, tumours acutely exposed to a PA–rich diet remain highly metastatic even when serially transplanted. This PA–induced prometastatic memory requires the FA transporter CD36 as well as the epigenetically stable deposition of histone H3 lysine 4 trimethylation by the methyltransferase Set1A/COMPASS. Genes with this metastatic memory predominantly relate to a neural signature that stimulates intratumor oligodendrogenesis and perineural invasion, two parameters strongly correlated with metastasis but etiologically poorly understood3-4. Mechanistically, induction of the epigenetic neural signature and its associated long-term boost in metastasis downstream of PA require the transcription factor EGR2 and the oligodendrocyte-stimulating peptide galanin. We provide evidence for a long-term epigenetic stimulation of metastasis by a dietary metabolite related to tumor innervation. In addition to underscoring the potential danger of eating large amounts of PA (and perhaps other saturated fats), our results reveal novel epigenetic and neural-related therapeutic strategies for metastasis. 3 biological replicates (2xVDH15 , 1xSCC25) with 3-4 techniclal replicates; Neural fraction cells from stroma derived from non-targeting shRNA (PLKO) and short heirpin silenced CD36 (shCD36) orthotopic oral tumor xenografts exposed to palmitic acid (PA)-rich, high-oleic acid (OA)-rich or control diet