Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function

By A. Viale, P. Pettazzoni, C. Lyssiotis, Haoqiang Ying, Nora S. Sanchez, M. Marchesini, A. Carugo, T. Green, S. Seth, V. Giuliani and 20 more. Nature, 2014

1,177 citations recorded by the source corpus.

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 (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.

Subfields: Cancer Research, Oncology

View Paper: https://www.semanticscholar.org/paper/819eeeb41f6e84dd5c00221a269e91238736c4ad

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Citations in the corpus

Autophagy in malignant transformation and cancer progression (2015, positive): “Thus, autophagy may also sustain tumor progression by preserving the viability of the CSC compartment and/or by promoting the persistence of dormant cancer cells (Viale et al , 2014).”
Metabolic reprogramming: the emerging concept and associated therapeutic strategies (2015, background): “Comprehensive analysis of metabolic pathways of survivors after chemotherapy revealed the prominent expression of genes that regulate mitochondrial function, autophagy and lysosome degradation activity, as well as a strong reliance on mitochondrial respiration and diminished dependence on the Warbur”
Oxidative Phosphorylation as an Emerging Target in Cancer Therapy (2018, background): “Transcriptomic and metabolic analyses of Ras-driven pancreatic ductal adenocarcinoma (PDAC) stem-like cells reveal a strong reliance onOXPHOSanddecreased glycolysis (19).”
Autophagy, Metabolism, and Cancer (2015, positive): “Small-molecule inhibitors of mitochondrial respiration suppress tumor growth, with growth only being restored upon recovery of normal mitochondrial function (78).”