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.

Effects of the Combined Treatment with a G-Quadruplex-Stabilizing Ligand and Photon Beams on Glioblastoma Stem-like Cells: A Magnetic Resonance Study

“…Lipid metabolism has been regarded as one of the key factors for the correct function of pathways involved in GSC fate and characteristics, e.g., chemotherapy evasion [ 56 , 57 ]. Enhanced lipid metabolism is essential for the survival, growth, and oncogenicity of GSCs [ 58 , 59 ]. GSCs seem to have increased levels of lipids and fatty acid oxidation (FAO)-related genes and these can maintain GSC self-renewal by modulating lipid and membrane synthesis, quenching ROS through NADPH production, and promoting chemo-resistance [ 23 , 59 ].…”

Epithelial-to-Mesenchymal Transition-Derived Heterogeneity in Head and Neck Squamous Cell Carcinomas

“…These clinically challenging occult tumor cells are highly problematic owing to a potentially stem-like and dormant phenotype associated with enhanced therapy resistance. Cancer stemness features are fostered via EMT and metabolic changes that are mostly associated with a rewiring towards glycolysis at the expense of oxidative phosphorylation [ 33 , 36 , 37 , 45 , 46 , 47 , 48 ]. In the following, diverse aspects of EMT in HNSCC will be summarized.…”

Irradiation Activates MZF1 to Inhibit miR-541-5p Expression and Promote Epithelial-Mesenchymal Transition (EMT) in Radiation-Induced Pulmonary Fibrosis (RIPF) by Upregulating Slug

“…Slug (Snai2) is essential for the development of EMT and is well-documented to promote EMT via the inhibition of E-cadherin transcription [ 11 , 12 ]. In prostate cancer (PCa), Slug plays an important role in the EMT of PCa as a direct effector of miR-3622a [ 13 ].…”