期刊：Nature
发表时间：2021/11/10
数字识别码：10.1038/s41586-021-04075-0
摘要：Fatty acid uptake and altered metabolism constitute hallmarks of metastasis1,2, 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 understood3,4. 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.
该研究由英国慈善机构全球癌症研究（Worldwide Cancer Research）提供部分资助，由西班牙巴塞罗那生物医学研究所（Institute for Research in Biomedicine，简称 IRB 研究所）领导。研究结果表明，棕榈油中常见的棕榈酸（palmitic acid，一种脂肪酸），可促进小鼠口腔癌和黑色素瘤的转移。而其他存在于橄榄油和亚麻籽等食物中，被称为油酸（omega-9）和亚油酸（omega-6）的脂肪酸则不会产生这种影响。此外，所测试的脂肪酸都不会增加发生癌症的风险。
该研究的资深作者，CREA 研究员、IRB 研究所干细胞和癌症实验室（Stem Cells and Cancer lab）负责人 Salvador Aznar-Benitah 与合作伙伴共同创立了一家公司，正在研发计划用于这类临床试验的抗体。这家公司名为 ONA Therapeutics 公司，最近从私人投资者那里获得了 3000 万欧元。研究人员希望该试验能够在未来几年内开始，以在几种不同类型的癌症中测试他们的新抗体。
巴塞罗那 IRB 高级研究组组长（Senior Group Leader）、ICREA 研究教授、该论文的资深作者 Salvador Aznar-Benitah 说：“要想确定转移性癌症患者采用哪种类型的饮食方案能够减慢癌症转移速度，我认为现在还为时过早。不过根据我们的结果，可以认为缺乏棕榈酸的饮食可以有效减缓转移过程，但还需要更多研究的工作来确定这一点。”
