Interplay between Metabolism Reprogramming and Epithelial-to-Mesenchymal Transition in Cancer Stem Cells

Simple Summary Tumor cells display important plasticity potential. Notably, tumor cells have the ability to change toward immature cells called cancer stem cells under the influence of the tumor environment. Importantly, cancer stem cells are a small subset of relatively quiescent cells that, unlike rapidly dividing differentiated tumor cells, escape standard chemotherapies, causing relapse or recurrence of cancer. Interestingly, these cells adopt a specific metabolism. Most often, they mainly rely on glucose uptake and metabolism to sustain their energy needs. This metabolic reprogramming is set off by environmental factors such as pro-inflammatory signals or catecholamine hormones (epinephrine, norepinephrine). A better understanding of this process could provide opportunities to kill cancer stem cells. Indeed, it would become possible to develop drugs that act specifically on metabolic pathways used by these cells. These new drugs could be used to strengthen the effects of current chemotherapies and overcome cancers with poor prognoses. Tumor cells display important plasticity potential, which contributes to intratumoral heterogeneity. Notably, tumor cells have the ability to retrodifferentiate toward immature states under the influence of their microenvironment. Importantly, this phenotypical conversion is paralleled by a metabolic rewiring, and according to the metabostemness theory, metabolic reprogramming represents the first step of epithelial-to-mesenchymal transition (EMT) and acquisition of stemness features. Most cancer stem cells (CSC) adopt a glycolytic phenotype even though cells retain functional mitochondria. Such adaptation is suggested to reduce the production of reactive oxygen species (ROS), protecting CSC from detrimental effects of ROS. CSC may also rely on glutaminolysis or fatty acid metabolism to sustain their energy needs. Besides pro-inflammatory cytokines that are well-known to initiate the retrodifferentiation process, the release of catecholamines in the microenvironment of the tumor can modulate both EMT and metabolic changes in cancer cells through the activation of EMT transcription factors (ZEB1, Snail, or Slug (SNAI2)). Importantly, the acquisition of stem cell properties favors the resistance to standard care chemotherapies. Hence, a better understanding of this process could pave the way for the development of therapies targeting CSC metabolism, providing new strategies to eradicate the whole tumor mass in cancers with unmet needs.