蛋白质组学揭示NNMT是癌症相关纤维细胞的主要代谢调节剂
Mark A Eckert1, Fabian Coscia2,3, Agnieszka Chryplewicz1
1Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, IL, USA.
Nature
|May 3, 2019
概括
这项研究表明,卵巢癌中甲基转移酶尼古丁胺胺 N- 甲基转移酶 (NNMT) 通过改变与癌症相关的纤维细胞功能来驱动转移. 针对NNMT为高度血清癌提供了潜在的治疗策略.
科学领域:
- 癌症学
- 蛋白质组学
- 癌症生物学
背景情况:
- 高度血清癌 (HGSC) 由于早期的腹部扩散,预后不佳.
- 了解瘤和体区对于破译HGSC转移至关重要.
- 现有的蛋白质基因组研究提供了快照,但缺乏系统的分组特异性分析.
研究的目的:
- 开发一种超低输入的蛋白质组工作流程,用于分析微切割的瘤和体区.
- 确定与HGSC转移相关的关键蛋白质特征.
- 研究已识别的结构蛋白在癌症进展和转移中的作用.
主要方法:
- 开发一种无标签的蛋白质组工作流程,用于分析固定在甲中的嵌入式细胞.
- 来自HGSC样本的瘤和膜区的微切割.
- 每个隔间的蛋白质组分析只有5000个细胞.
- 功能性测试,以评估肌肉NNMT对癌症相关纤维细胞 (CAF) 表型和卵巢癌进展的影响.
主要成果:
- 在疾病进展过程中瘤蛋白质保持稳定.
- 转移相关的肌表现出保存的蛋白质特征,特别是包括尼古丁胺 N- 甲基转移酶 (NNMT).
- 对于CAF表型来说,Stromal NNMT表达是必不可少的,并且足以促进卵巢癌的迁移,扩散,生长和转移.
- 在CAF中,NNMT导致S- 腺甲的耗尽和基因组甲基化的减少,导致瘤层中广泛的基因表达变化.
结论:
- 超低输入蛋白质学可以识别疾病表型的关键驱动因素.
- 尼古丁胺N- 甲基转移酶 (NNMT) 是CAF分化和HGSC进展的中心代谢调节剂.
- 对于卵巢癌治疗,Stromal NNMT 是一个潜在的治疗点.
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