A computational investigation of stress-dependent growth in breast cancer

Cancer growth supresses several key regulatory checkpoints that control cell division and tissue homeostasis, thereby leading to uncontrolled proliferation. Cancer cells retain sensitivity to mechanical loading, although the underlying cell-scale mechanisms driving this behaviour have not yet been established. In this highly interdisciplinary thesis, we first propose a hydromechanical model for cell growth as governed by actively controlled osmolarity. We explore cell volume dynamics under various regimes, including extracellular osmotic shocks and applied loading. By validating our hydromechanical model against experimental data, we show that mitosis is dependent on a cell’s ability to attain a certain volume, and loading inhibits growth and prevents cells from reaching this volume. This hydromechanical model is integrated into a spherically-constrained agent-based cell modelling framework to investigate the growth and remodelling of cancer monolayers. Our model demonstrates that a disruption of the balance between hydrostatic and osmotic pressures across the membrane at the cellular level leads to spatially heterogenous cell volume and proliferation. By further expanding the hydromechanical model into a three-dimensional agent-based deformable cell framework, we explicitly model contact and mechanical interactions across cellular interfaces. Our model reveals how the interplay between local confinement stress and cytoskeletal dynamics influences cell volume, morphology, and the overall evolution of tumour spheroids. Confinement and biomechanical feedback from the extracellular matrix are analysed through a neural network-accelerated finite element solver. By evaluating solver performance across diverse geometries and loading conditions, we demonstrate broad applicability to many problem domains. We combine the deformable cell model with the finite element solver to model mechanosensitive spheroid growth within the extracellular matrix, and by validating our predictions against in-vitro experimental data, we show that mechanosensitive spheroid growth can arise from a sizing checkpoint for mitosis. Spheroid growth within the extracellular matrix exerts an outward force, stretching and deforming the surrounding matrix, giving rise to radial and circumferential stresses. These stresses in turn induce high levels of mechanical loading on the spheroid and increase hydrostatic pressure at the cellular level. High hydrostatic pressure overcomes the competition with osmotic pressure driven by biomolecule synthesis, prevents cells from surpassing the critical volume required for mitosis, and ultimately suppresses proliferation in highly confined environments. 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.

Funder

Irish Research Council
Univeristy of Galway

Publisher

University of Galway

Rights

CC BY-NC-ND

cbn

Collections

University of Galway Theses (PhD Theses)