Mechanisms Underlying the Coordination of EMT and Glycolysis Mediated by Hypoxia and Glucose.

Hypoxia is a hallmark of the tumor microenvironment. Under hypoxia, HIF-1α accumulates and promotes both epithelial-mesenchymal transition (EMT) and glycolysis depending on glucose levels. However, how EMT and glycolysis are coordinated by oxygen and glucose abundance is still not well understood. Here, we developed an integrated model to investigate the mechanism underlying the regulation of EMT and glycolysis at varying oxygen and glucose levels. We focused on how the interplay between EMT and glycolysis maintains cell phenotypes. Our results show that hypoxia and sufficient glucose facilitate the transition of cells toward an invasion-associated mesenchymal-glycolytic phenotype. Moreover, enhanced glycolysis promotes the completion of EMT and reinforces the intermediate states. Under glucose-sufficient conditions, the reciprocal promotion between EMT and glycolysis may convert transient hypoxia into persistent mesenchymal memory that maintains the mesenchymal phenotype after reoxygenation. Our work clarifies how metabolic microenvironmental fluctuations are transformed into durable invasion-associated phenotypic states. Our work may provide insights into therapies that target both the EMT and glycolysis pathways.