Figure 1. Mitochondrial metabolism and possible mechanisms of metformin sensitivity in pancreatic tumor-initiating cells. (A) Increased mitochondrial gene expression in pancreatic cancer cells compared to PanIN cells. An analysis by microarray was performed as described in Deschenes-Simard et al. and analysed with the FlexArray 1.6.3 software (GEO accession number: GSE57566). The fold increase of relative mRNA levels is indicated in red inside brackets. (B) Potential mechanisms explaining the specific toxicity of metformin on tumor-initiating cells. The inhibition of the TCA cycle by metformin may; impair ROS-dependent signaling, induce bioenergetic stress and reduce the production of critical metabolites required for tumor-initiating cell survival. In addition, metformin may increase the abundance of Akkermansia muciniphila in the gastrointestinal tract, thus protecting against the translocation of LPS in the systemic circulation.