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

Abstract

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.

Keywords: cancer stem cell; catecholamines; cell plasticity; epithelial-to-mesenchymal transition; metabolism reprogramming.

Figure 1

Tumor microenvironment drives epithelial-to-mesenchymal transition and tumor progression. Under the effects of genetic alterations and/or the influence of the microenvironment (inflammatory cytokines, hypoxic factors, catecholamines), differentiated tumor cells can undergo epithelial-to-mesenchymal transition and metabolism reprogramming. These alterations lead to the development of cancer stem cells that escape programmed cell death, evade the host immune system, and resist standard care chemotherapies. ECM: extracellular matrix; CSC: cancer stem cell; EMT: epithelial-to-mesenchymal transition; OXPHOS: oxidative phosphorylation.

Figure 2

Glycolysis- or OXPHOS-dependent cancer stem cells. Depending on tissue location and quiescence/proliferation status, CSC preferentially use glycolysis or OXPHOS to meet their energy needs. Glycolysis-dependent CSC are characterized by increased lactate production and/or glutaminolysis. Catecholamines favor the glycolytic profile by increasing the expression of glucose transporters and key glycolytic enzymes (HK2, LDHA). Lower use of OXPHOS reduces the ROS production. In OXPHOS-dependent CSC, the TCA cycle is fed from glucose, glutamine, and fatty acids. Metabolic-targeted therapies under investigation are indicated in green. Red arrows indicate intensified signaling pathways and blue arrows indicate reduced signaling pathways. CSC: cancer stem cell; OXPHOS: oxidative phosphorylation, ROS: reactive oxygen species; HK2: hexokinase 2; LDHA: lactate dehydrogenase A; GSH: glutathione; GLUT, glucose transporter; GlnT, glutamine transporter; MCT, monocarboxylate transporter; CI: complex I of the respiratory chain.