抗瘤基因剥离的胰腺癌细胞取决于线粒体功能
Andrea Viale1, Piergiorgio Pettazzoni1, Costas A Lyssiotis2
11] Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [3].
Nature
|August 15, 2014
概括
胰腺癌细胞在KRAS通路的抑制中幸存下来,依赖于线粒体呼吸. 通过氧化酸化抑制剂准这种脆弱性可以防止瘤复发.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 癌症新陈代谢 癌症新陈代谢
背景情况:
- 胰腺管腺癌 (PDAC) 的预后不佳,KRAS突变是关键的驱动因素.
- 向瘤源途径可以导致瘤缩,但通常会导致由于存活的癌细胞而复发.
- 通过PDAC细胞生存瘤基因切除的机制仍然不完全理解.
研究的目的:
- 调查突变KRAS在PDAC维护中的作用,并确定存活的瘤细胞中的漏洞.
- 探索休眠PDAC细胞的代谢依赖性,使其在瘤基因抑制后复发.
主要方法:
- 在p53的背景下利用了突变Kras (Kras(G12D)) 的新型诱导性小鼠模型.
- 在眠瘤细胞上进行了转录和代谢分析,这些细胞在瘤基因切除后幸存下来.
- 评估了幸存细胞对氧化酸化抑制剂的敏感性.
主要成果:
- 一个潜伏的PDAC细胞亚群,表现出癌症干细胞特征,在瘤基因切除中幸存下来.
- 这些幸存的细胞表现出 mitochondrial 功能,自和 lysosome 活动的增加,依赖氧化酸化来获得能量.
- 幸存的细胞对氧化酸化抑制剂具有很高的敏感性,可有效抑制瘤复发.
结论:
- 负责复发的休眠PDAC细胞依赖氧化酸化来生存.
- 结合对KRAS通路和线粒体呼吸的向,为胰腺癌提供了一个有前途的治疗策略.
- 抑制氧化酸化可以防止PDAC模型中的瘤复发.
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