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

Differentiated epithelial cancer cells depend on oxidative phosphorylation (OXPHOS).^9,10 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)^98,99 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 CSCs⁹⁹ 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.