(391e) Modeling Population Dynamics of Cancer Stem Cells with Epithelial-Mesenchymal Transition

Cancer stem cells (CSCs) are tumor cells that possess stem cell-like characteristics of self-renewal and multipotency. In CSC model, CSCs are differentiated into heterogeneous population of tumor cells, and these differentiated non-tumorigenic cells constitute bulk of tumor with lack of self-renewal capacity and limited proliferation potential. In this context, studying cancer cell population during tumor initiation/progression/metastasis with the concept of CSCs might bring further insight into molecular drug target and clinical strategies. However, it has been recently revealed that there exists plasticity in certain tumors in that the phenotypically differentiated cells can de-differentiate and acquire stem cell features. Induction of epithelial-mesenchymal transition (EMT) is thought to being crucial to this regain of CSCs phenotype, and can be regarded as one of the important tools in maintaining CSCs pool in tumors. Despite the importance of EMT in tumor hierarchy and metastasis, so far, there is no clear explanation on the role of EMT in population dynamics of cancers and little is known about therapeutic implication of it due to difficulties as well as uncertainty in identifying CSCs experimentally. Under these circumstances, mathematical model can give great insight to unravel complicated nature of hierarchical tumor heterogeneity. Therefore, in this study, we first tried to construct comprehensive population dynamics model of tumors by introducing EMT and other known phenomena, such as dormancy of CSCs or regulatory feedback loops. To investigate the effects of various biological factors, sensitivity analysis of model parameters was conducted and we could obtain reasonable prediction of tumor hierarchy driven by heterogeneous populations of CSCs and non-CSCs. Then, the tumor population dynamics were explored under different therapeutic scenarios of conventional chemotherapy, chemotherapy targeting CSCs, or combinational chemotherapy employing both of them. The results clearly illustrate the improved efficacy of combinational chemotherapeutic agents on heterogeneous populations and address several issues of central importance to the success treatment of human malignancies.