PLOS Computational Biology
2026-06-24
DOI: HASH:9be92ab037451935d495bf32ca57dd16
by Daniela Volpatto, Sandro Gepiro Contaldo, Simone Pernice, Marco Beccuti, Francesca Cordero, Roberta Sirovich
Intratumor heterogeneity (ITH) arises from the combined effects of genetic alterations, clonal interactions, and environmental constraints, and plays a central role in therapeutic resistance and disease progression. While ITH has been extensively documented in empirical tumor data, the scientific debate regarding the biological mechanisms underlying this heterogeneity remains complex, highlighting the need for cancer evolution models that are sufficiently flexible and sophisticated to reproduce the observed behaviors and to give insights on the unobserved ones. Here, we present a stochastic modelling framework for tumor evolution that integrates genotypic inheritance with phenotype driven functional traits and resource mediated competition. Mutational events are associated with functional capabilities such as altered proliferation, increased mutation rates, limit evasion potential or enhanced control over shared resources, allowing multiple genotypes to converge on similar phenotypes. The model explicitly tracks subclonal lineages while incorporating environmental constraints that modulate growth and competition. The framework is defined through a mathematically rigorous construction and is accompanied by an efficient simulation algorithm. To facilitate exploration and reproducibility, we provide an open-source graphical user interface that allows users to configure model parameters, run simulations, and inspect clonal genealogies and population dynamics without requiring direct interaction with the underlying code. Using this model, we illustrate how ecological feedbacks can shape clonal dynamics over time, supporting an interpretation in which early tumor growth is dominated by stochastic expansion, while later evolution increasingly reflects selection for traits that alleviate environmental constraints. Rather than constituting a new evolutionary paradigm, this behaviour demonstrates how well-documented biological patterns can emerge naturally from a unified stochastic and ecological description. Overall, our approach offers a flexible and extensible platform for investigating how chance, functional traits, and environmental interactions jointly govern tumor heterogeneity.