Quantification of the Underlying Mechanisms and Relationships Among Cancer, Metastasis, and Differentiation and...

Recurrence and metastasis have been regarded as two of the greatest obstacles to cancer therapy. Cancer stem cells (CSCs) contribute to cancer development, with the distinctive features of recurrence and resistance to popular treatments such as drugs and chemotherapy. In addition, recent discoveries suggest that the epithelial mesenchymal transition (EMT) is an essential process in normal embryogenesis and tissue repair, as well as being a required step in cancer metastasis. Although there are many indications of the connections between metastasis and stem cells, these have often been studied separately or at most bi-laterally, not in an integrated way. In this study, we aimed to explore the global mechanisms and interrelationships among cancer, development, and metastasis, which are currently poorly understood. First, we constructed a core gene regulatory network containing specific genes and microRNAs of CSCs, EMT, and cancer. We uncovered seven distinct states emerging from the underlying landscape, denoted normal, premalignant, cancer, stem cell, CSC, lesion, and hyperplasia. Given the biological definition of each state, we also discuss the metastasis ability of each state. We show how and which types of cells can be transformed to a cancer state, and the connections among cancer, CSCs, and EMT. The barrier height and flux of the kinetic paths are explored to quantify how and which cells switch stochastically between the states. Our landscape model provides a quantitative approach to reveal the global mechanisms of cancer, development, and metastasis.