Tumors evolve under constantly changing microenvironmental conditions, and a key major mechanism by which cancer cells adapt to fluctuating environments is stochastic phenotypic switch via epithelial-mesenchymal plasticity (EMP). Here we demonstrate the existence of EMP in human breast epithelial cell lines and assess the fitness of E and M cells in environments that fluctuate between favorable and harsh conditions. We then develop a theoretical framework for analysis of tumor evolution with E-M stochastic phenotypic switch that integrates the behaviors of E and M cells. We characterize the outcomes of tumor evolution via three characteristic times describing i) tumor growth, ii) phenotypic adaptation and iii) fluctuations of the environment. We identify a tradeoff between tumor growth and survival, with different phenotype switching rates maximizing each of these objectives. An anticancer therapeutic strategy is proposed based on tumor survival analysis, revealing that blocking mesenchymal to epithelial transition, rather than epithelial to mesenchymal transition, is critical under fluctuating conditions. Thus, this study elucidates fundamental evolutionary mechanisms of tumor phenotypic adaptation in fluctuating environments with potentially important clinical implications.
Babajanyan, S., Wolf, Y. I., Canevarolo, R. R., Sudalagunta, P. R., Silva, A. S., Koonin, E., Persi, E.
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