Nature：依赖于呼吸的癌症干细胞

万能的干细胞

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期刊名：Nature    日期：2014-10-31
. f% k' P0 T& g' L/ N8 x% q5 _KRAS 突变代表着胰腺导管腺癌的一个促成事件。以这一通道为目标进行治疗可导致肿瘤退化，但复发的频率表明，一部分肿瘤细胞即便在没有致癌信号的情况下也会幸存下来。Giulio Draetta及同事利用一个Kras/p53小鼠模型(在其中致癌基因Kras的表达可以被关闭)发现，在致癌基因切除后幸存了下来、造成肿瘤复发的休眠肿瘤细胞子类群依靠“氧化性磷酸化”(OXPHOS)来存活。这些细胞对OXPHOS抑制因子(它们能抑制肿瘤复发)高度敏感，说明将KRAS通道和线粒体呼吸一起作为治疗目标，对于治疗胰腺癌也许会有效。
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% j: z! N# ]! `; a" U3 y! h' p原文摘要：5 G  z, o$ X$ \% _/ C

# s! V& L4 b9 ^6 z! O: |. k# Loncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function5 G$ w2 w: r+ U
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Andrea Viale, Piergiorgio Pettazzoni, Costas A. Lyssiotis, Haoqiang Ying, Nora Sánchez,Matteo Marchesini, Alessandro Carugo, Tessa Green, Sahil Seth, Virginia Giuliani, Maria Kost-Alimova, Florian Muller, Simona Colla, Luigi Nezi, Giannicola Genovese, Angela K. Deem, Avnish Kapoor, Wantong Yao, Emanuela Brunetto, Ya’an Kang, Min Yuan, John M. Asara, Y. Alan Wang, Timothy P. Heffernan, Alec C. Kimmelman, A, z- T( b8 |9 G0 {/ u

+ q# W3 z  i; |+ Q/ hPancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in western countries, with a median survival of 6 months and an extremely low percentage of long-term surviving patients.KRAS mutations are known to be a driver event of PDAC1, but targeting mutant KRAS has proved challenging2. Targeting oncogene-driven signalling pathways is a clinically validated approach for several devastating diseases3, 4. Still, despite marked tumour shrinkage, the frequency of relapse indicates that a fraction of tumour cells survives shut down of oncogenic signalling5, 6. Here we explore the role of mutant KRAS in PDAC maintenance using a recently developed inducible mouse model of mutated Kras1 (KrasG12D, herein KRas) in a p53LoxP/WT background. We demonstrate that a subpopulation of dormant tumour cells surviving oncogene ablation (surviving cells) and responsible for tumour relapse has features of cancer stem cells and relies on oxidative phosphorylation for survival. Transcriptomic and metabolic analyses of surviving cells reveal prominent expression of genes governing mitochondrial function, autophagy and lysosome activity, as well as a strong reliance on mitochondrial respiration and a decreased dependence on glycolysis for cellular energetics. Accordingly, surviving cells show high sensitivity to oxidative phosphorylation inhibitors, which can inhibit tumour recurrence. Our integrated analyses illuminate a therapeutic strategy of combined targeting of the KRAS pathway and mitochondrial respiration to manage pancreatic cancer.（doi: 10.1038/nature13611）
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* y; {3 c" P  M对应Nature杂志： 2014年10月30日 Nature杂志精选