Fatty acid uptake and altered metabolism constitute hallmarks of metastasis^1,2, yet evidence of the underlying biology, as well as whether all dietary fatty acids are prometastatic, is lacking. Here we show that dietary palmitic acid (PA), but not oleic acid or linoleic acid, promotes metastasis in oral carcinomas and melanoma in mice. Tumours from mice that were fed a short-term palm-oil-rich diet (PA), or tumour cells that were briefly exposed to PA in vitro, remained highly metastatic even after being serially transplanted (without further exposure to high levels of PA). This PA-induced prometastatic memory requires the fatty acid transporter CD36 and is associated with the stable deposition of histone H3 lysine 4 trimethylation by the methyltransferase Set1A (as part of the COMPASS complex (Set1A/COMPASS)). Bulk, single-cell and positional RNA-sequencing analyses indicate that genes with this prometastatic memory predominantly relate to a neural signature that stimulates intratumoural Schwann cells and innervation, two parameters that are strongly correlated with metastasis but are aetiologically poorly understood^3,4. Mechanistically, tumour-associated Schwann cells secrete a specialized proregenerative extracellular matrix, the ablation of which inhibits metastasis initiation. Both the PA-induced memory of this proneural signature and its long-term boost in metastasis require the transcription factor EGR2 and the glial-cell-stimulating peptide galanin. In summary, we provide evidence that a dietary metabolite induces stable transcriptional and chromatin changes that lead to a long-term stimulation of metastasis, and that this is related to a proregenerative state of tumour-activated Schwann cells.

脂肪酸摄取和代谢改变构成转移的标志^1,2，但缺乏潜在生物学的证据，以及是否所有膳食脂肪酸都是前转移的。在这里，我们显示膳食棕榈酸 (PA)，而不是油酸或亚油酸，促进了小鼠口腔癌和黑色素瘤的转移。来自喂食短期富含棕榈油的饮食 (PA) 的小鼠的肿瘤，或在体外短暂暴露于 PA 的肿瘤细胞，即使在连续移植后仍保持高度转移性（没有进一步暴露于高水平的 PA） . 这种 PA 诱导的前转移记忆需要脂肪酸转运蛋白 CD36，并且与甲基转移酶 Set1A（作为 COMPASS 复合物 (Set1A/COMPASS) 的一部分）对组蛋白 H3 赖氨酸 4 三甲基化的稳定沉积有关。块，^3,4。从机制上讲，与肿瘤相关的雪旺氏细胞会分泌一种专门的促再生细胞外基质，其消融会抑制转移的起始。PA 诱导的这种原神经特征的记忆及其对转移的长期促进都需要转录因子 EGR2 和神经胶质细胞刺激肽甘丙肽。总之，我们提供的证据表明饮食代谢物诱导稳定的转录和染色质变化，从而导致长期刺激转移，并且这与肿瘤激活的雪旺细胞的再生状态有关。