Decoding the coupled decision-making of the epithelial-mesenchymal transition and metabolic reprogramming in cancer

Abstract

Cancer metastasis relies on an orchestration of multiple traits driven by different functional interacting modules including metabolism and epithelial-mesenchymal transition (EMT). Cancer cells can adjust their metabolism during metastasis by increasing oxidative phosphorylation without compromising glycolysis, acquiring a hybrid metabolic phenotype (W/O). Often required by metastasis, cancer cells engage EMT and can acquire a hybrid epithelial/mesenchymal (E/M) phenotype. Both the W/O and E/M states are associated with high metastatic potentials. Many regulatory links coupling metabolism and EMT have been identified, but how these two modules regulate each other remains largely unexplored. Here, we investigate the coupled decision-making networks of metabolism and EMT, and systematically analyzed the effect of their crosstalk. This crosstalk can exhibits synergistic or antagonistic effects on the acquisition and stability of different coupled metabolism-EMT states. Strikingly, the aggressive E/M-W/O state can be enabled and stabilized by the crosstalk irrespective of these hybrid states availability in individual metabolism or EMT modules. To acquire an E/M-W/O state, the W/O state emerges first, followed by the E/M state, suggesting metabolism can drive EMT. Our work emphasizes the mutual activation between metabolism and EMT, providing an important step towards understanding the multi-faceted nature of cancer metastasis.