Multiscale Modeling of Spheroid Tumors: Effect of Nutrient Availability on Tumor Evolution

Recent years have
revealed a large number of complex mechanisms
and interactions that drive the development of malignant tumors. Tumor
evolution is a framework that explains tumor development as a process
driven by survival of the fittest, with tumor cells of different properties
competing for limited available resources. To predict the evolutionary
trajectory of a tumor, knowledge of how cellular properties influence
the fitness of a subpopulation in the context of the microenvironment
is required and is often inaccessible. Computational multiscale-modeling
of tissues enables the observation of the full trajectory of each
cell within the tumor environment. Here, we model a 3D spheroid tumor
with subcellular resolution. The fitness of individual cells and the
evolutionary behavior of the tumor are quantified and linked to cellular
and environmental parameters. The fitness of cells is solely influenced
by their position in the tumor, which in turn is influenced by the
two variable parameters of our model: cell–cell adhesion and
cell motility. We observe the influence of nutrient independence and
static and dynamically changing nutrient availability on the evolutionary
trajectories of heterogeneous tumors in a high-resolution computational
model. Regardless of nutrient availability, we find a fitness advantage
of low-adhesion cells, which are favorable for tumor invasion. We
find that the introduction of nutrient-dependent cell division and
death accelerates the evolutionary speed. The evolutionary speed can
be increased by fluctuations in nutrients. We identify a distinct
frequency domain in which the evolutionary speed increases significantly
over a tumor with constant nutrient supply. The findings suggest that
an unstable supply of nutrients can accelerate tumor evolution and,
thus, the transition to malignancy.