Link between glucose metabolism and epithelial-to-mesenchymal transition drives triple-negative breast cancer migratory heterogeneity

Intracellular and environmental cues result in heterogeneous cancer cell populations with different metabolic and migratory behaviors. Although glucose metabolism and epithelial-to-mesenchymal transition have previously been linked, we aim to understand how this relationship fuels cancer cell migration. We show that while glycolysis drives single-cell migration in confining microtracks, fast and slow cells display different migratory sensitivities to glycolysis and oxidative phosphorylation inhibition. Phenotypic sorting of highly and weakly migratory subpopulations (MDA+, MDA−) reveals that more mesenchymal, highly migratory MDA+ preferentially use glycolysis while more epithelial, weakly migratory MDA− utilize mitochondrial respiration. These phenotypes are plastic and MDA+ can be made less glycolytic, mesenchymal, and migratory and MDA− can be made more glycolytic, mesenchymal, and migratory via modulation of glucose metabolism or EMT. These findings reveal an intrinsic link between EMT and glucose metabolism that controls migration. Identifying mechanisms fueling phenotypic heterogeneity is essential to develop targeted metastatic therapeutics.