Eco-Evolutionary Dynamics of Proliferation Heterogeneity: A Phenotype-Structured Model for Tumor Growth and Treatment Response.

Intra-tumor heterogeneity in proliferation rates fundamentally influences cancer progression and treatment resistance. To investigate how continuous phenotypic variation shapes eco-evolutionary dynamics, we develop a phenotype-structured partial differential equation framework that explicitly models proliferation heterogeneity as a dynamic trait. Our model integrates three key biological principles: (1) phenotypic diffusion capturing heritable variation in proliferation rates, (2) global resource competition enforcing density-dependent growth constraints, and (3) an experimentally grounded life-history trade-off linking elevated proliferation to increased mortality. Using adaptive dynamics, we derive the optimum proliferation rate in a growing tumor, showing that the optimal phenotype dynamically shifts toward slower proliferation as tumors approach carrying capacity under control condition. We perform in silico treatment simulations for four different treatment regimes (uniform targeting, low-, mid-, and high-proliferation targeting) to show how therapeutic selective pressures reshape fitness landscapes. While all treatments slow down tumor growth, they induce divergent evolutionary trajectories. We connect these dynamics with changes in mean proliferation rates during and after treatment. Our work establishes a predictive, evolutionarily grounded framework for understanding how therapy reshapes tumor proliferation landscapes, offering a mechanistic basis for designing strategies that anticipate and counteract adaptive resistance.