Viale Andrea, Pettazzoni Piergiorgio, Lyssiotis Costas A, Ying Haoqiang, Sánchez 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
1] 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].
Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
Nature. 2014 Oct 30;514(7524):628-32. doi: 10.1038/nature13611. Epub 2014 Aug 10.
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. KRAS mutations are known to be a driver event of PDAC, but targeting mutant KRAS has 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 mutant KRAS in PDAC maintenance using a recently developed inducible mouse model of mutated Kras (Kras(G12D), herein KRas) in a p53(LoxP/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.
胰腺导管腺癌（PDAC）是西方国家最致命的癌症之一，中位生存期为6个月，长期存活患者的比例极低。已知KRAS突变是PDAC的驱动事件，但靶向突变型KRAS已被证明具有挑战性。针对致癌基因驱动的信号通路是一种经临床验证的治疗多种严重疾病的方法。然而，尽管肿瘤明显缩小，但复发频率表明，一部分肿瘤细胞在致癌信号关闭后仍能存活。在这里，我们使用最近开发的在p53（LoxP/WT）背景下的可诱导突变型Kras（Kras（G12D），以下简称KRas）小鼠模型，探索突变型KRAS在PDAC维持中的作用。我们证明，致癌基因消融后存活的休眠肿瘤细胞亚群（存活细胞）是肿瘤复发的原因，具有癌症干细胞的特征，并且依赖氧化磷酸化来维持生存。对存活细胞的转录组学和代谢分析揭示了控制线粒体功能、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糖酵解的细胞能量依赖的降低。因此，存活细胞对氧化磷酸化抑制剂表现出高度敏感性，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一种联合靶向KRAS通路和线粒体呼吸来治疗胰腺癌的策略。
