Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function

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 KangMin Yuan, John M. Asara, Y. Alan Wang, Timothy P. Heffernan, Alec C. Kimmelman, Huamin Wang, Jason B. Fleming, Lewis C. Cantley, Ronald A. DePinho, Giulio F. Draetta

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)628-632
Number of pages5
JournalNature
Volume514
Issue number7524
DOIs
Publication statusPublished - Oct 30 2014

ASJC Scopus subject areas

  • Medicine(all)

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  • Cite this

    Viale, A., Pettazzoni, P., Lyssiotis, C. A., Ying, H., Sánchez, N., Marchesini, M., Carugo, A., Green, T., Seth, S., Giuliani, V., Kost-Alimova, M., Muller, F., Colla, S., Nezi, L., Genovese, G., Deem, A. K., Kapoor, A., Yao, W., Brunetto, E., ... Draetta, G. F. (2014). Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature, 514(7524), 628-632. https://doi.org/10.1038/nature13611