Exploring the relationship between vascular remodelling and tumour growth using agent-based modelling

Abstract

We develop a multiscale agent-based model (ABM) to investigate the effect that mechanical interactions between proliferating tumour cells and the surrounding vasculature have on the oxygen supply to the tumour microenvironment (TME), the tumours growth dynamics, and its response to radiotherapy. Our model extends existing models of tumour spheroid growth by incorporating vessel deformation due to mechanical forces between vessel walls and neighbouring tumour cells. These forces generate an effective pressure which compresses vessels, driving occlusion and pruning. This, in turn, leads to a hypoxic oxygen landscape which stimulates angiogenesis. A key feature of our model is the treatment of mechanical cell interactions with the tumour microenvironment, which we represent with two forces. The first is Stokes drag which is widely used in ABMs to represent resistance to cell movement. The second is a friction force which accounts for resistance due to the continual breaking and reforming of cell-extracellular matrix (ECM) adhesions. The importance of this friction force is demonstrated by numerical simulation. When Stokes drag dominates, pressure gradients dissipate across the tissue and vessel compression is negligible. By contrast, as the strength of the friction force increases, larger pressure gradients form, leading to significant vessel compression. We perform extensive numerical simulations to investigate how model parameters that control vascular remodelling and friction influence tumour vascularisation, which we spatially quantify using the cross-pair correlation function. This, in turn, alters the oxygen landscape and drives changes in tumour morphology. Finally, we highlight the importance of accounting for both mechanisms when simulating tumour responses to treatment with radiotherapy. We observe that vascular remodelling critically alters the tumours susceptibility to treatment and post-radiotherapy regrowth. Tumour regrowth is especially impacted by vessel remodelling, with certain vascular landscapes able to rebound quickly post-radiotherapy, resulting in fast tumour regrowth. Author SummaryWe have created an agent-based model (ABM) that accounts for mechanical interactions between tumour cells and associated vasculature. The model simulates vessel occlusion and pruning due to compression by neighbouring tumour cells; and growth of new vessels in response to hypoxia. Incorporating pressure-mediated vessel occlusion into our ABM required development of a friction force representing cell-extracellular matrix (ECM) adhesion. Through numerical simulations, we show that when friction is neglected, pressure gradients dissipate throughout the tissue and vessel compression is negligible. By contrast, as the strength of the friction force increases, larger pressure gradients form, leading to significant vessel compression. We perform extensive model simulations, to investigate how changes in the oxygen landscape caused by vascular remodelling affect the tumours growth dynamics and composition. We show further how vessel remodelling influences a tumours response to radiotherapy. We find tumour regrowth to be especially sensitive to vessel remodelling, with certain vascular landscapes growing rapidly post-radiotherapy, and accelerating tumour regrowth.