MYC/PGC-1α Balance Determines the Metabolic Phenotype and Plasticity of Pancreatic Cancer Stem Cells

• DOI: 10.1016/j.cmet.2015.08.015
• Publication Date: 2015-09-12T06:24:25Z
• Authors: Patricia Sancho; Emma Burgos-Ramos; Alejandra Tavera; Tony Bou Kheir; Petra Jagust; Matthieu Schoenhals; David Barneda; Katherine Sellers; Ramon Campos-Olivas; Osvaldo Graña; Catarina R. Viera; Mariia Yuneva; Bruno Sainz; Christopher Heeschen
• Keywords: 0301 basic medicine; Physiology; Cancer de pancreas; Mice, Nude; Antineoplastic Agents; MYC/PGC-1a; Oxidative Phosphorylation; Proto-Oncogene Proteins c-myc; Mice; 03 medical and health sciences; Antigens, CD; Animals; Humans; AC133 Antigen; Molecular Biology; Gene Library; Glycoproteins; Cell Biology; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Metformin; Mitochondria; 3. Good health; Pancreatic Neoplasms; Phenotype; Drug Resistance, Neoplasm; Neoplastic Stem Cells; RNA Interference; Peptides

The anti-diabetic drug metformin targets pancreatic cancer stem cells (CSCs), but not their differentiated progenies (non-CSCs), which may be related to distinct metabolic phenotypes. Here we conclusively demonstrate that while non-CSCs were highly glycolytic, CSCs were dependent on oxidative metabolism (OXPHOS) with very limited metabolic plasticity. Thus, mitochondrial inhibition, e.g., by metformin, translated into energy crisis and apoptosis. However, resistant CSC clones eventually emerged during treatment with metformin due to their intermediate glycolytic/respiratory phenotype. Mechanistically, suppression of MYC and subsequent increase of PGC-1α were identified as key determinants for the OXPHOS dependency of CSCs, which was abolished in resistant CSC clones. Intriguingly, no resistance was observed for the mitochondrial ROS inducer menadione and resistance could also be prevented/reversed for metformin by genetic/pharmacological inhibition of MYC. Thus, the specific metabolic features of pancreatic CSCs are amendable to therapeutic intervention and could provide the basis for developing more effective therapies to combat this lethal cancer.