西班牙巴塞罗那科学技术研究院Salvador Aznar Benitah、Gloria Pascual和美国西北大学Ali Shilatifard课题组合作取得一项新突破。他们的最新研究发现膳食棕榈酸通过雪旺细胞促进癌症转移前记忆。该研究于2021年11月10日发表于国际学术期刊《自然》杂志。
研究人员发现膳食棕榈酸(PA)而非油酸或亚油酸促进小鼠口腔癌和黑色素瘤的转移。短期高棕榈油(PA)喂养小鼠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（没有进一步暴露于高水平PA）能力。这种PA诱导的转移前记忆需要脂肪酸转运蛋白CD36，并且与甲基转移酶Set1A（COMPASS 复合物(Set1A/COMPASS)组分）和组蛋白H3 4位赖氨酸三甲基化的积累有关。大量、单细胞和位置RNA测序分析表明，具有这种前转移记忆的基因主要与激活瘤内雪旺细胞和神经支配细胞相关，这两个参数与转移密切相关，但在病理学上却知之甚少。
从机制上讲，肿瘤相关的雪旺氏细胞分泌一种专门的促再生细胞外基质，其缺失抑制了转移的发生。PA诱导的这种原神经特征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。该研究表明，饮食代谢物会诱导稳定的转录和染色质变化，从而保持肿瘤细胞长期转移的能力，其与肿瘤激活雪旺氏细胞的再生状态有关。
研究人员表示，脂肪酸摄取和代谢改变是癌症转移的标志，但缺乏支持该理论的潜在生物学证据；同时，尚不知晓是否所有膳食脂肪酸都具有促转移作用。
附：英文原文
Title: Dietary palmitic acid promotes a prometastatic memory via Schwann cells
Author: Pascual, Gloria, Domnguez, Diana, Elosa-Bayes, Marc, Beckedorff, Felipe, Laudanna, Carmelo, Bigas, Claudia, Douillet, Delphine, Greco, Carolina, Symeonidi, Aikaterini, Hernndez, Inmaculada, Gil, Sara Ruiz, Prats, Neus, Bescs, Coro, Shiekhattar, Ramin, Amit, Moran, Heyn, Holger, Shilatifard, Ali, Benitah, Salvador Aznar
Issue&Volume: 2021-11-10
Abstract: 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.
DOI: 10.1038/s41586-021-04075-0
Source: https://www.nature.com/articles/s41586-021-04075-0
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
