Towards decoding the coupled decision-making of metabolism and epithelial-to-mesenchymal transition in cancer

Abstract

Cancer cells have the plasticity to adjust their metabolic phenotypes for survival and metastasis. A developmental programme known as epithelial-to-mesenchymal transition (EMT) plays a critical role during metastasis, promoting the loss of polarity and cell-cell adhesion and the acquisition of motile, stem-cell characteristics. Cells undergoing EMT or the reverse mesenchymal-to-epithelial transition (MET) are often associated with metabolic changes, as the change in phenotype often correlates with a different balance of proliferation versus energy-intensive migration. Extensive crosstalk occurs between metabolism and EMT, but how this crosstalk leads to coordinated physiological changes is still uncertain. The elusive connection between metabolism and EMT compromises the efficacy of metabolic therapies targeting metastasis. In this review, we aim to clarify the causation between metabolism and EMT on the basis of experimental studies, and propose integrated theoretical-experimental efforts to better understand the coupled decision-making of metabolism and EMT.

Fig. 1. Crosstalk between EMT and metabolism in cancer.

The purple arrows represent metabolic fluxes. The black arrows/bar-headed arrows represent transcriptional regulation. The black dotted bar-headed arrows represent ncRNA-mediated regulation. The brown arrows/bar-headed arrows represent epigenetic regulations. The purple dotted arrows represent the transportation of molecules that mediate the interaction between EMT and metabolic reprogramming. EMT-inducing signals, EMT-TFs and EMT-associated ncRNAs can directly regulate the transcription or translation of metabolic enzymes and transporters. In turn, the metabolic intermediates can facilitate epigenetic modification of EMT-associated genes or proteins. For example, the EMT-TFs Slug/Twist can repress mitochondrial respiration via suppression of SDH. SDH suppression leads to accumulation of succinate. Succinate accumulation can cause DNA hypermethylation by inhibiting TET2, and subsequently promotes EMT. More details about the EMT-metabolism crosstalk can be found in sections “how does EMT affect metabolism?” and “how does cancer metabolism affect EMT”. GLUT glucose transporter, FATP fatty acid transporter protein, MCT monocarboxylate transporter, LDHA lactate dehydrogenase A, PDH pyruvate dehydrogenase, PC pyruvate carboxylase, OAA oxaloacetic acid, α-KG α-ketoglutarate, CPT carnitine palmitoyltransferase, GDH glutamate dehydrogenase, GLS glutaminase, ncRNA non-coding RNA, EMT-TF EMT-inducing transcription factor. The Figure was created by BioRender.com.

Fig. 2. Hypothetical coupling of EMT and metabolic reprogramming during the acquisition of stemness.

Differentiated epithelial cancer cells depend on oxidative phosphorylation (OXPHOS).^, Upon undergoing EMT, these cells can increase their glycolytic activity as needed to acquire stemness and become hybrid E/M-like cancer stem cells (CSCs; OXPHOS^high/glycolysis^high, proliferative). The hybrid E/M-like CSCs can either decrease their OXPHOS activity to transition into mesenchymal-like CSCs (glycolysis^high, quiescent)^, or decrease their glycolytic activity and lose stemness to transition into the differentiated mesenchymal cancer cells (OXPHOS^high). Note that being labelled OXPHOS^high does not determine the extent to which fatty acid oxidation is operative, which could differ between different types of differentiated cancer cell. Quiescent mesenchymal-like CSCs (glycolysis^high) can either increase their OXPHOS activity to become hybrid E/M-like CSCs or switch from glycolysis to OXPHOS and differentiate into mesenchymal cancer cells; these cells might undergo dedifferentiation to become mesenchymal-like CSCs. It will be interesting to investigate whether differentiated epithelial cancer cells can directly transition into mesenchymal-like CSCs without passing through hybrid E/M phenotypes. The Figure was created by BioRender.com.

Fig. 3. A systematic pipeline to elucidate the connection between EMT and metabolic reprogramming.

Mathematical modelling approaches have provided critical insights into the dynamics of EMT and metabolism and predicted the acquisition of stable hybrid phenotypes by cancer cells. The AMPK/HIF-1/ROS model (bottom left) is an initial effort to understand how genetic regulation interacts with metabolic fluxes. The miR-34/SNAIL/miR-200/ZEB model (bottom right) was used in the initial studies that proposed that hybrid epithelial/mesenchymal (E/M) phenotypes can constitute an end point of EMT. The predicted hybrid metabolic phenotype and hybrid E/M phenotype have been validated by several in vitro and in vivo studies, respectively.^,, With further advances in single-cell multi-omics, acquisition of the transcriptomics and metabolomics profiles of the same single cell can facilitate the understanding of EMT–metabolism coupling. Through the integration of mathematical modelling, data analysis and experimental studies, the nuanced EMT–metabolism connection can gradually be elucidated. The Figure was created by BioRender.com.