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Phenotypic heterogeneity along the epithelial-mesenchymal (E-M) axiscontributes to cancer metastasis and drug resistance. Recent experimentalefforts have collated detailed time-course data on the emergence and dynamicsof E-M heterogeneity in a cell population. However, it remains unclear howdifferent possible processes interplay in shaping the dynamics of E-Mheterogeneity: a) intracellular regulatory interaction among biomolecules, b)cell division and death, and c) stochastic cell-state transition (biochemicalreaction noise and asymmetric cell division). Here, we propose a CellPopulation Balance (Partial Differential Equation (PDE)) based model thatcaptures the dynamics of cell population density along the E-M phenotypic axisdue to abovementioned multi-scale cellular processes. We demonstrate howpopulation distribution resulting from intracellular regulatory networksdriving cell-state transition gets impacted by stochastic fluctuations in E-Mregulatory biomolecules, differences in growth rates among cell subpopulations,and initial population distribution. Further, we reveal that a lineardependence of the cell growth rate on the population heterogeneity issufficient to recapitulate the faster in vivo growth of orthotopic injectedheterogeneous E-M subclones reported before experimentally. Overall, our modelcontributes to the combined understanding of intracellular and cell-populationlevels dynamics in the emergence of E-M heterogeneity in a cell population.

An integrative phenotype-structured partial differential equation model for the population dynamics of epithelial-mesenchymal transition