While the Warburg effect (aerobic glycolysis) has long been recognized as a hallmark of cancer cells, accumulating evidence reveals that CSCs exhibit metabolic plasticity, converting between glycolysis, OXPHOS, and other metabolic routes, such as fatty acid oxidation (FAO), depending on microenvironmental cues.228 This plasticity is intimately regulated by the Notch, Hedgehog, and PI3K/AKT/mTOR networks; in turn, metabolic intermediates can influence the activity of these pathways (Fig. 5b). This evidence concerns the gene PIK3CA and cancer.