Pancreatic cancer stem cells exhibit adaptation of mitochondrial physiology based on their energetic requirements

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer with an overall 5-year survival rate of less than 9%. Over the past decades, few advances in PDAC treatment have been made. Furthermore, approximately 80% of PDAC patients are diagnosed at an advanced stage and mostly have no effective treatment options. The high aggressiveness of PDAC is associated with increased resistance to conventional therapies, early progression to metastatic disease, and a significant recurrence rate. All these aggressive traits are linked to the presence of a subpopulation of cancer cells with a greater tumorigenic capacity, generically called cancer stem cells (CSCs). CSCs are typically in a quiescent state that, under certain stimuli, can proliferate and give rise to a new progeny of tumor cells. Given that a single CSC could regenerate the whole tumor, the study of CSCs hallmarks is crucial for the design of new therapeutic strategies to prevent cancer progression and relapse. Some studies show that CSCs exhibit increased glycolytic rate and decreased mitochondrial function, whereas other studies report a dependence of these cells on mitochondrial oxidative phosphorylation, suggesting that CSCs likely present a heterogeneous metabolic profile. Metabolic plasticity would not be possible without mitochondrial remodelling to maintain cellular homeostasis. Although mitochondrial functions are deeply studied in cancer, the role of this organelle in the development and maintenance of CSCs has not yet been clarified. To determine the role of mitochondria in CSCs over longer periods, which may reflect more accurately their quiescent state, we studied the mitochondrial physiology in CSCs at three de-differentiation stages (at 2, 4, and 8 weeks of culture) using a PDAC cellular model previously described by our group. We found that CSCs show a significant increase in mitochondrial mass, more mitochondrial fusion, and higher mRNA expression of genes involved in mitochondrial biogenesis than parental cells. These changes are accompanied by increased ROS generation, regulation of the activities of electron transport chain complexes and supercomplexes assembly. Furthermore, the proteins OPA1 and IF1, which are involved in mitochondrial dynamics and inhibition of ATPase synthase, respectively, are overexpressed in CSCs and modulate the tumorsphere formation. Finally, we identified that lomerizine, a calcium channel blocker and an inhibitor of mitochondrial respiration, exhibits potent anticancer activity, particularly against pancreatic CSCs. Our findings indicate that CSCs undergo mitochondrial remodelling during the stemness acquisition process, which could be exploited to find vulnerabilities in mitochondrial function as a promising therapeutic target against pancreatic CSCs.