Exposing the underlying relationship of cancer metastasis to metabolism and epithelial-mesenchymal transitions

Summary 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-mesenchymal transition (EMT), and cancer metastasis. We constructed a metabolism-EMT-metastasis regulatory network and quanti_ed its underlying landscape. We identi_ed four attractors, characterizing epithelial, abnormal metabolic, mesenchymal, and metastatic cell states, respectively. Importantly, we identi_ed an abnormal metabolic state. Based on the transition path theory, we quanti_ed the kinetic transition paths among these di_erent cell states. Our results for landscape and paths indicate that metastasis is a sequential process: cells tend to _rst change their metabolism, then activate the EMT and eventually reach the metastatic state. This demonstrates the importance of the temporal order for di_erent gene circuits switching on or o_ during metastatic progression of cancer cells, and underlines the cascading regulation of metastasis through an abnormal metabolic intermediate state.