Mechanical influences on in silico tumor evolution

Abstract

Experimental insight and conceptual understanding of tumor growth are steadily growing and leading to new therapeutic interventions. Experiments and clinical studies are able to link single-cell properties to macroscopic tumor attributes. The development of cellular subpopulations in heterogeneous tumors can be understood as an evolutionary system with different cell types competing over both space and nutrients. However, to predict the growth trajectory and development of a tumor, fitness and trade-offs of cell properties in the context of the surroundings are required and often inaccessible. The optimum of the evolutionary trajectory provides a target for intervention, but can mostly not be identified. We propose that the optimal value of cellular properties is influenced by the tumor surrounding. Computational multiscale-modeling of tissue enables the observation of the trajectory of each cell while modeling the tumor surrounding. We model a 3D spheroid tumor and the fitness of individual cells and the evolutionary behavior of the tumor are quantified and linked to global parameters. Cell–cell adhesion and cell motility are two important mechanical properties for cell development and used as free parameters. Mechanical properties alone are able to drive the tumor towards low adhesion.We implement a dynamically changing nutrient surrounding representing the fluctuating blood-supply through blood vessel collapse and angiogenesis. We find that the evolutionary speed depends on the frequency of the fluctuations. We identify a frequency domain in which the evolutionary speed is significantly increased over a tumor with constant nutrient supply. The findings suggest that mechanically-induced fluctuations can accelerate tumor evolution. Author summary Limited space and nutrients together with competing cell types drive an evolutionary process inside tumors. This process selects for the fittest cell types and optimizes the growing behavior for its local surroundings. An expanding tumor exerts mechanical forces on its cells and its surroundings, leading to a fluctuating nutrient supply through collapsing blood vessels. Here, we observe the influence of a dynamically changing surrounding on the evolutionary behavior of heterogeneous tumors in a high-resolution computational model. We find that the evolutionary speed depends on the frequency of the fluctuations and a fitness advantage of low-adhesion cells.