An agent-based 3D model of non-genetic adaptation in cancer tissues under electrical, mechanical, and hypoxic stress

The research described in this article investigates the non-genetic adaptation mechanisms in cancer tissues subjected to electrical, mechanical, and hypoxic stress. Until now, the combined effects of these stressors on the tumor's phenotype under three-dimensional conditions have not been well understood.

In this study, the authors developed an agent-based model of a tumor that takes into account vascular oxygen supply, a globally applied electric field, mechanical crowding and compression cues, phenotype transitions, cell growth, mitosis, cell death, and the inheritance of adaptive memory across cell divisions. The simulation showed that tumors go through a three-stage process: the onset of necrosis, a temporary collapse of the living tumor mass, and then a partial regrowth, all while there is a gradual increase in the fraction of adapted cells.

Applying continuous electrical stimulation leads to a dose-dependent reduction in the live tumor mass, but significantly increases the proportion of adapted cells, with only minor changes in the necrotic burden. This response is strongly influenced by mechanical forces and alters the adaptive capacity of the tumor. Pulsed electrical stimulation further highlights that the electric field's amplitude and timing together determine the memory phenomena, phenotypic diversification, and recovery of growth in the model.

The study concludes that the interplay between local oxygen availability, mechanical constraints, electrical forcing, and history-dependent phenotype transitions can generate distinct patterns of phenotypic heterogeneity at the tissue level. Furthermore, both the magnitude of the stimuli and their temporal protocol affect the population structure, indicating that the history of physical stress may play a crucial role in the adaptive dynamics of spatially organized tumor models.