Stress-dependent growth of breast cancer models emerges from a cellular volume checkpoint

Abstract

Mechanoresponsive cell proliferation is a feature of growing tumours, despite the suppression of many other regulatory checkpoints in cancer, but the underlying cell-scale mechanisms driving this behaviour have not yet been established. In this study we propose a biophysical model for cell growth as governed by actively controlled osmolarity, which we integrate with a discrete particle framework to simulate growth and remodelling of breast cancer spheroids. Confinement and biomechanical feedback from the extracellular environment are analysed through a neuralnetwork-accelerated finite element solver. Combining the framework with experiments, our model reveals that stress-dependent spheroid growth can arise from a sizing checkpoint for mitosis. Under sufficient extracellular loading, cell growth is restricted by high hydrostatic forces in competition with osmotic pressure from biomolecule synthesis, which prevents cells from surpassing a critical volume. Our model provides new insight into mechanosensitive growth arrest in breast cancer, potentially serving as a computational tool for analysing growth in a wider range of normal and malignant biological tissues.