Cancer stemness and progression: mitochondria on the stage

The idea that mitochondrial functions correlate with tumor malignancy recently arose together with the indication that respiration and processing of different nutrients, as well as the generation of reactive oxygen species, play a mandatory role during key steps of tumor progression. While the Warburg scenario, depending on the availability of glycolytic intermediates capable to fuel anabolic pathways, has been associated with the metabolic demand of growing cells, a metabolic reprogramming to enhanced mitochondrial function has been related to increased aggressiveness. Indeed, mitochondrial oxidants are mandatory to engage epithelial/mesenchymal transition [1], while oxidative phosphorylation and ability to exploit nutrients by respiration sustain dormancy, resistance to therapy and tumor relapse [2]. In line with the above idea, in three very recent OncoTarget papers of Michael Lisanti's laboratory, the mitochondria-addicted cancer phenotype has been correlated with the achievement of stem-like traits [3-5]. They found that the number of mitochondria, as revealed by MitoTracker staining, correlates with stemness, suggesting that cancer stem cells (CSC) may be selected via mitochondrial staining. Noteworthy, a relatively large size of cancer cells was also found associated with stemness and mitochondrial number/function [3]. The latter observation is in contradiction with the idea that biomass increase correlates with the Warburg metabolic profile, which supports anabolic pathways in terms of aminoacid and nucleotide synthesis. Such a paradox is only apparent, as pyruvate kinase M2 (PKM2), a key regulator of the accumulation of glycolytic intermediates needed for cell growth and historically associated with a Warburg profile, is also an upstream regulator of the transcriptional pathway leading to the generation and functional upgrading of mitochondria [1]. Thus, PKM2 lies at the crossroads between biomass accumulation and mitochondria functionalization. On the other hand, Myc has been involved in cell reprogramming towards the mitochondria-based glutamine metabolism, as well as in the control of protein biosynthesis leading to biomass increase. Both observations reveal that the link between biomass increase and mitochondrial functions is strong, although clearly underestimated at present. Lisanti's group strengthened the association of the mitochondria-rich/anabolic/motile phenotype with stem cell traits using a telomerase expression-based model. High telomerase expression was found correlated with number/function of mitochondria and cell size/biomass [4]. Nutrient sensing through sirtuins and PGC1α-mediated increased mitochondrial biogenesis are likely to play a central role in the acquisition of the mitochondria-rich/stem-like/anabolic phenotype, and therefore to support CSC resistance to therapy [6]. Finally, FGF3 and Wnt1 secreted by neighboring cells are able to reprogram cancer …