Targeting the Metabolic Reprogramming That Controls Epithelial-to-Mesenchymal Transition in Aggressive Tumors

Abstract

The epithelial-to-mesenchymal transition (EMT) process allows the trans-differentiation of a cell with epithelial features into a cell with mesenchymal characteristics. This process has been reported to be a key priming event for tumor development and therefore EMT activation is now considered an established trait of malignancy. The transcriptional and epigenetic reprogramming that governs EMT has been extensively characterized and reviewed in the last decade. However, increasing evidence demonstrates a correlation between metabolic reprogramming and EMT execution. The aim of the current review is to gather the recent findings that illustrate this correlation to help deciphering whether metabolic changes are causative or just a bystander effect of EMT activation. The review is divided accordingly to the catabolic and anabolic pathways that characterize carbohydrate, aminoacid, and lipid metabolism. Moreover, at the end of each part, we have discussed a series of potential metabolic targets involved in EMT promotion and execution for which drugs are either available or that could be further investigated for therapeutic intervention.

Keywords: OXPHOS; TCA cycle; Warburg metabolism; amino acid; epithelial-to-mesenchymal transition; lipids; metabolic reprogramming; oncometabolites.

Figure 1

General features of epithelial-to-mesenchymal transition (EMT). The transition of epithelial cells toward a mesenchymal phenotype, induced by several environmental or soluble factors, is characterized by the loss of cell–cell contact and cell polarity, which disrupts the epithelial architecture and endows the mesenchymal cells with migratory and invasive competences. EMT is accompanied by the modulation of well-known markers, among which the loss of epithelial marker E-cadherin, induced by the upregulation of its transcriptional repressors (i.e., Snail1/2, Twist, ZEB1/2), is one of the priming event. The concomitant acquisition of mesenchymal markers sustains and stabilizes the newly acquired phenotype.

Figure 2

The metabolic features of epithelial-to-mesenchymal transition (EMT). Several components of the molecular pathways driving EMT have a clear impact on cell metabolism and vice versa, resulting in a metabolic rewiring which sustains the EMT transcriptional program. EMT-committed cancer cells could rely on an aerobic glycolytic metabolism or could shift toward the more efficient oxidative phosphorylation (OXPHOS), dependent on tumor type and/or tumor stage. Here, we have highlighted in red circles/ellipses EMT transcriptional factors that are affected by the metabolites reported in different tumor types.

Figure 3

Epithelial-to-mesenchymal transition (EMT) and lipid metabolism: interconnection and targeting. Several EMT-induced stimuli modulate the content of different classes of lipids, with an impact on both cell metabolism and membrane composition. Some EMT inducers [i.e., tumor necrosis factor-α (TNF-α), hepatocyte growth factor (HGF)] promote lipogenesis by stimulating fatty acid synthase (FASN) and leading to an increase in glicerophospholipids (which are transferred to the cell membrane and regulate lipid rafts organization) and in triacylglycerol [stored in lipid drops as a reservoir of fatty acids (FAs) for catabolic or anabolic purpose]. On the other hand, other reports support a role for transforming growth factor-β (TGF-β)-derived Snail1 in the suppression of the lipogenic program by repressing FASN expression, thus diverting acetyl-CoA toward catabolic pathways, such as the tricarboxylic acid (TCA) cycle. TGF-β-induced EMT also correlates with a reduction in the pool of sphingolipids by (i) the downregulation of the expression of ceramide synthase, which results in the reduction of ceramide levels; (ii) the lowering of ganglioside content due to the control of EMT-related transcription factors (i.e., SNAIL1, Twist, Zeb1) on the expression of genes encoding ganglioside metabolizing enzymes. These events result in an increase of plasma membrane fluidity and destabilization of lipid rafts, to which significantly concurs also the upregulation of cholesterol content. Pharmacological inhibitors of cholesterol synthesis (i.e., statins), the administration of alkyl phospholipid drugs (the so-called “dis-rafters”), and nutritional factors, such as the ω-3 polyunsaturated FA docosahexaenoic acid, result in the stabilization of lipid raft and in the reduction of membrane fluidity, thereby counteracting EMT, invasion, and the acquisition of stem-like features.