# Cancer evolution simulation identifies possible principles underlying intratumor heterogeneity

## TL;DR

This study uses a simulation model to explore how cancer evolves and identifies factors that contribute to diversity within tumors.

## Contribution

The study introduces a new simulation model and identifies evolutionary principles that explain intratumor heterogeneity.

## Key findings

- Multiple driver genes of moderate strength shape subclonal structures through positive natural selection.
- High mutation rates and stem cell hierarchies lead to high intratumor heterogeneity via neutral evolution.
- Fractal patterns characterize extremely high intratumor heterogeneity.

## Abstract

Cancer arises from accumulation of somatic mutations and accompanying evolutionary selection for growth advantage. During the evolutionary process, an ancestor clone branches into multiple clones, yielding intratumor heterogeneity. However, principles underlying intratumor heterogeneity have been poorly understood. Here, to explore the principles, we built a cellular automaton model, termed the BEP model, which can reproduce the branching cancer evolution in silico. We then extensively searched for conditions leading to high intratumor heterogeneity by performing simulations with various parameter settings on a supercomputer. Our result suggests that multiple driver genes of moderate strength can shape subclonal structures by positive natural selection. Moreover, we found that high mutation rate and a stem cell hierarchy can contribute to extremely high intratumor heterogeneity, which is characterized by fractal patterns, through neutral evolution. Collectively, This study identified the possible principles underlying intratumor heterogeneity, which provide novel insights into the origin of cancer robustness and evolvability.