Modeling Epithelial-Mesenchymal Transitions in Metastatic Cancer

Abstract

Cancer metastasis is responsible for more than 90% of cancer deaths. Yet, understanding epithelial mesenchymal transition (EMT) during cancer metastasis remains a major challenge in cancer biology. It is now established that cells use genetic regulatory circuits to make functional decisions of whether to undergo EMT or not. In this study, we constructed a theoretical model of the circuitry involved in the EMT. The core regulatory unit for the decision consists of two highly interconnected chimeric modules - the miR-34/SNAIL and the miR-200/ZEB mutual-inhibition feedback circuits. We developed a theoretical framework for modeling microRNA-based circuit and applied it to study the chimeric modules. We showed that the miR-34/SNAIL module functions as a noise-buffering signal integrator, and the miR-200/ZEB module functions as a three-way switch, allowing not only for the epithelial and mesenchymal phenotypes, but also for a hybrid phenotype with mixed epithelial and mesenchymal characteristics. We further studied EMT in a multi-cell environment by coupling the EMT circuit to cancer-related signaling pathways and by including cell-cell communications. Our model explains recent data on the observation of unusual intermediates with specialized cell behavior, such as collective migration, and phonotypical heterogeneity of the EMT observed in various lung cancer cell lines.