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.