On the morphological stability of multicellular tumour spheroids growing in porous media

Abstract.: Multicellular tumour spheroids (MCTSs) are extensively used as in vitro system models for investigating the avascular growth phase of solid tumours. In this work, we propose a continuous growth model of heterogeneous MCTSs within a porous material, taking into account a diffusing nutrient from the surrounding material directing both the proliferation rate and the mobility of tumour cells. At the time scale of interest, the MCTS behaves as an incompressible viscous fluid expanding inside a porous medium. The cell motion and proliferation rate are modelled using a non-convective chemotactic mass flux, driving the cell expansion in the direction of the external nutrients’ source. At the early stages, the growth dynamics is derived by solving the quasi-stationary problem, obtaining an initial exponential growth followed by an almost linear regime, in accordance with experimental observations. We also perform a linear-stability analysis of the quasi-static solution in order to investigate the morphological stability of the radially symmetric growth pattern. We show that mechano-biological cues, as well as geometric effects related to the size of the MCTS subdomains with respect to the diffusion length of the nutrient, can drive a morphological transition to fingered structures, thus triggering the formation of complex shapes that might promote tumour invasiveness. The results also point out the formation of a retrograde flow in the MCTS close to the regions where protrusions form, that could describe the initial dynamics of metastasis detachment from the in vivo tumour mass. In conclusion, the results of the proposed model demonstrate that the integration of mathematical tools in biological research could be crucial for better understanding the tumour’s ability to invade its host environment. Graphical abstract: [Figure not available: see fulltext.