GSE182867
Dietary palmitic acid promotes a prometastatic memory based on Schwann Cell activation
Metastasis is promoted by fatty acid (FA) uptake and metabolism 1-2 . 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 in oral carcinomas and melanoma, 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. Bulk, single cell and positional RNA sequencing indicate that genes with this metastatic memory predominantly relate to a neural  signature that stimulates activation of intratumor Schwann cells and perineural invasion, two parameters strongly correlated with metastasis but etiologically poorly understood 3-4 . Mechanistically, tumour-associated Schwann cells secrete a specialized pro-regenerative extracellular matrix reminiscent of perineuronal nets, which when ablated strongly inhibits metastatic colonization. The induction of the epigenetic neural signature and its associated long-term boost in metastasis downstream of PA require the transcription factor EGR2 and the glial cell-stimulating peptide galanin. We provide evidence for a long-term epigenetic stimulation of metastasis by a dietary metabolite related to a pro-regenerative state of tumour-activated Schwann cells. In addition to underscoring the potential danger of eating large amounts of PA, our results reveal novel epigenetic and neural-related therapeutic strategies for metastasis. Overall design: Single-cell RNA sequencing and Visium Spatial Transcriptomics was used to explore changes in the tumor microenvironment in response to a fatty acid rich diet. Samples from mouse models under control and palmitic acid rich diets in control and CD36 knockouts.