小柯机器人

代谢差异导致肿瘤转移潜能差异
2019-12-19 13:35

美国德克萨斯大学西南医学中心Sean J. Morrison和Ralph J. DeBerardinis研究组合作发现代谢异质性导致黑色素瘤转移潜能的差异。2019年12月18日,《自然》在线发表了这项成果。

他们表示由于MCT1转运蛋白功能的差异,黑色素瘤细胞之间的代谢差异赋予了其转移潜力差异。在源自患者的异种移植物中的体内同位素示踪分析显示,有效和无效转移的黑色素瘤之间在营养处理方面存在差异,循环乳酸是有效转移中肿瘤乳酸的更主要来源。有效转移的MCT1水平较高,而抑制MCT1可以降低乳酸摄取。

MCT1抑制作用对原发性皮下肿瘤的生长几乎没有影响,但导致循环性黑色素瘤细胞耗竭并降低了患者来源异种移植物和小鼠黑色素瘤的转移性疾病负担。另外,抑制MCT1抑制了氧化戊糖磷酸途径并增加了活性氧的水平。

抗氧化剂阻断了MCT1抑制转移的作用。来自相同黑素瘤的MCT1high细胞和MCT1- / low细胞形成皮下肿瘤的能力相似,但静脉注射后MCT1high细胞形成更多的转移。癌细胞之间的代谢差异因此赋予了转移潜力差异,因为转移细胞依赖MCT1来控制氧化应激。

据悉,转移需要癌细胞的代谢改变,而其如何变化尚不清楚。

附:英文原文

Title: Metabolic heterogeneity confers differences in melanoma metastatic potential

Author: Alpaslan Tasdogan, Brandon Faubert, Vijayashree Ramesh, Jessalyn M. Ubellacker, Bo Shen, Ashley Solmonson, Malea M. Murphy, Zhimin Gu, Wen Gu, Misty Martin, Stacy Y. Kasitinon, Travis Vandergriff, Thomas P. Mathews, Zhiyu Zhao, Dirk Schadendorf, Ralph J. DeBerardinis, Sean J. Morrison

Issue&Volume: 2019-12-18

Abstract: Metastasis requires cancer cells to undergo metabolic changes that are poorly understood13. Here we show that metabolic differences among melanoma cells confer differences in metastatic potential as a result of differences in the function of the MCT1 transporter. In vivo isotope tracing analysis in patient-derived xenografts revealed differences in nutrient handling between efficiently and inefficiently metastasizing melanomas, with circulating lactate being a more prominent source of tumour lactate in efficient metastasizers. Efficient metastasizers had higher levels of MCT1, and inhibition of MCT1 reduced lactate uptake. MCT1 inhibition had little effect on the growth of primary subcutaneous tumours, but resulted in depletion of circulating melanoma cells and reduced the metastatic disease burden in patient-derived xenografts and in mouse melanomas. In addition, inhibition of MCT1 suppressed the oxidative pentose phosphate pathway and increased levels of reactive oxygen species. Antioxidants blocked the effects of MCT1 inhibition on metastasis. MCT1high and MCT1/low cells from the same melanomas had similar capacities to form subcutaneous tumours, but MCT1high cells formed more metastases after intravenous injection. Metabolic differences among cancer cells thus confer differences in metastatic potential as metastasizing cells depend on MCT1 to manage oxidative stress. Differences in MCT1 function among melanoma cells confer differences in oxidative stress resistance and metastatic potential.

DOI: 10.1038/s41586-019-1847-2

Source:

https://www.nature.com/articles/s41586-019-1847-2

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
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

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