Exposing the Underlying Relationship of Cancer Metastasis to Metabolism and Epithelial-Mesenchymal Transitions

Cancer is a disease governed by the underlying gene regulatory networks. The hallmarks of cancer have been proposed to characterize the cancerization, e.g., abnormal metabolism, epithelial to mesenchymal transition (EMT), and cancer metastasis. We constructed a metabolism-EMT-metastasis regulatory network and quantified its underlying landscape. We identified four attractors, characterizing epithelial, abnormal metabolic, mesenchymal, and metastatic cell states, respectively. Importantly, we identified an abnormal metabolic state. Based on the transition path theory, we quantified the kinetic transition paths among these different cell states. Our results for landscape and paths indicate that metastasis is a sequential process: cells tend to first change their metabolism, then activate the EMT and eventually reach the metastatic state. This demonstrates the importance of the temporal order for different gene circuits switching on or off during metastatic progression of cancer cells and underlines the cascading regulation of metastasis through an abnormal metabolic intermediate state.