Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function.
Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function.
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DOI：
10.1038/nature13611
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发表时间：
2014-10-30
期刊：
影响因子：
64.8
通讯作者：
Draetta, Giulio F.
中科院分区：
文献类型：
--
作者：
Viale, Andrea;Pettazzoni, Piergiorgio;Lyssiotis, Costas A.;Ying, Haoqiang;Sanchez, Nora;Marchesini, Matteo;Carugo, Alessandro;Green, Tessa;Seth, Sahil;Giuliani, Virginia;Kost-Alimova, Maria;Muller, Florian;Colla, Simona;Nezi, Luigi;Genovese, Giannicola;Deem, Angela K.;Kapoor, Avnish;Yao, Wantong;Brunetto, Emanuela;Kang, Ya'an;Yuan, Min;Asara, John M.;Wang, Y. Alan;Heffernan, Timothy P.;Kimmelman, Alec C.;Wang, Huamin;Fleming, Jason B.;Cantley, Lewis C.;DePinho, Ronald A.;Draetta, Giulio F.
胰腺导管腺癌（Pancreatic ductal adenocarcinoma，PDAC）是西方国家最致命的癌症之一，中位生存期为6个月，长期存活患者的百分比极低。靶向癌基因驱动的信号通路是一种临床验证的方法，用于治疗几种毁灭性疾病。尽管肿瘤明显缩小，但复发的频率表明一部分肿瘤细胞在致癌信号转导关闭后存活下来。在此，我们使用最近开发的在p53 LoxP/WT背景下的突变Kras（KrasG 12 D，本文中KRas）的诱导型小鼠模型来探索突变Kras在PDAC维持中的作用。我们证明了一个亚群的休眠肿瘤细胞生存癌基因消融（存活细胞）和负责肿瘤复发的癌症干细胞的功能，并依赖于氧化磷酸化的生存。存活细胞的转录组学和代谢分析揭示了支配线粒体功能、自噬和溶酶体活性的基因的显著表达，以及对线粒体呼吸的强烈依赖和对细胞能量的糖酵解的依赖性降低。因此，存活的细胞显示出对氧化磷酸化抑制剂的高敏感性，氧化磷酸化抑制剂可以抑制肿瘤复发。我们的综合分析阐明了联合靶向KRAS通路和线粒体呼吸来管理胰腺癌的治疗策略。
Pancreatic 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.KRASmutations are known to be a driver event of PDAC, but targeting mutantKRAShas proved challenging. Targeting oncogene-driven signalling pathways is a clinically validated approach for several devastating diseases,. Still, despite marked tumour shrinkage, the frequency of relapse indicates that a fraction of tumour cells survives shut down of oncogenic signalling,. Here we explore the role of mutantKRASin PDAC maintenance using a recently developed inducible mouse model of mutatedKras(KrasG12D, herein KRas) in a p53LoxP/WTbackground. 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 theKRASpathway and mitochondrial respiration to manage pancreatic cancer.
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影响因子：
23.9
作者：
Lagadinou, Eleni D.;Sach, Alexander;Callahan, Kevin;Rossi, Randall M.;Neering, Sarah J.;Minhajuddin, Mohammad;Ashton, John M.;Pei, Shanshan;Grose, Valerie;O'Dwyer, Kristen M.;Liesveld, Jane L.;Brookes, Paul S.;Becker, Michael W.;Jordan, Craig T.
通讯作者：
Jordan, Craig T.
影响因子：
14.8
作者：
通讯作者：
--
抑制线粒体翻译是人类急性髓样白血病的治疗策略。
影响因子：
50.3
作者：
Skrtić M;Sriskanthadevan S;Jhas B;Gebbia M;Wang X;Wang Z;Hurren R;Jitkova Y;Gronda M;Maclean N;Lai CK;Eberhard Y;Bartoszko J;Spagnuolo P;Rutledge AC;Datti A;Ketela T;Moffat J;Robinson BH;Cameron JH;Wrana J;Eaves CJ;Minden MD;Wang JC;Dick JE;Humphries K;Nislow C;Giaever G;Schimmer AD
通讯作者：
Schimmer AD
影响因子：
9.9
作者：
Gaglio, Daniela;Metallo, Christian M.;Chiaradonna, Ferdinando
通讯作者：
Chiaradonna, Ferdinando
影响因子：
10.5
作者：
Guo, Jessie Yanxiang;Chen, Hsin-Yi;White, Eileen
通讯作者：
White, Eileen