BPS2026 - Object engulfment by cellular aggregates (“spherophagy”): Computational simulations with applications to destruction of solid tumors

Inspired by developmental biology and heuristic computational observations, we propose and simulate how cellular aggregates can engulf objects larger than individual cells, provided these objects possess comparable adhesivity and deformability. We termed this process spherophagy, a phenomenon which was sporadically observed but has received little systematic attention. We simulated avascular tumors using the CompuCell3D modeling platform. 1 We further compared isolated spheroids (model 1) with tumors surrounded by a layer of normal, non-dividing cells, akin to a stromal cell layer (model 2). 2 . We also implemented hydrogel particles (HP) with surface adhesion mimicking cell-matrix binding. Once engulfed by the tumor, HP was activated in either one of two distinct modes: (1) as drug-releasing depots, or (2) as glucose-absorbing sinks. In the first case, engulfed HP steadily released a diffusible cytotoxic agent into the tumor, inducing cell death. In the second case, HP acted as draining glucose from the local environment and accelerating cancer-cell starvation. First, we established the conditions under, which tumor spheroids fully engulfed HP and demonstrated how this process can lead to complete tumor destruction. In both models, the tumors engulfed the HP and disrupted tumor cells viability, though the presence of stroma expectedly modified the engulfment kinetics and nutrient gradients. These results suggest spherophagy could serve as a “Trojan horse” therapeutic strategy: HP engineered with adhesive ligands could be designed to infiltrate and be engulfed by tumors, where they either release therapeutic payloads or deprive cancer cells of nutrients to starvation. Our results motivate experimental validation and highlight spherophagy as a new approach for solid tumor therapy. 1 Swat, M.H. et al. (2015). PLoS. One 10, e0127972. 2 Bustamante, D.J. et al. (2021). Biofabrication . 10.1088/1758-5090/abe025.