Abstract
Cancer cells manoeuvre through extracellular matrices (ECMs) using different invasion modes, including single cell and collective cell invasion. These modes rely on MMP-driven ECM proteolysis to make space for cells to move. How cancer-associated alterations in ECM influence the mode of invasion remains unclear. Further, the sensitivity of the two invasion modes to MMP dynamics remains unexplored. In this paper, we address these open questions using a multiscale hybrid computational model combining ECM density-dependent MMP secretion, MMP diffusion, ECM degradation by MMP and active cell motility. Our results demonstrate that in randomly aligned matrices, collective cell invasion is more efficient than single cell invasion. Although increase in MMP secretion rate enhances invasiveness independent of cell–cell adhesion, sustenance of collective invasion in dense matrices requires high MMP secretion rates. However, matrix alignment can sustain both single cell and collective cell invasion even without ECM proteolysis. Similar to our in-silico observations, increase in ECM density and MMP inhibition reduced migration of MCF-7 cells embedded in sandwich gels. Together, our results indicate that apart from cell intrinsic factors (i.e., high cell–cell adhesion and MMP secretion rates), ECM density and organization represent two important extrinsic parameters that govern collective cell invasion and invasion plasticity.
Highlights
What is the role of cell–cell adhesion with respect to extracellular matrix (ECM) remodeling and maintaining invasiveness of cancer cells? What is a more efficient mode of invasion, and when would the cells prefer to switch from one mode to the other? How does ECM confinement and proteolytic abilities collectively dictate the mode and efficiency of cell invasion? In short, the existing models address the effect of various aforementioned factors on avascular cancer cell invasion, they do not elucidate how these factors conspire together to dictate the mode and efficiency of invasion, and what invasion strategies cells may flexibly follow upon tuning these factors[13,30]
Our results suggest that while loss of cell–cell adhesion leads to individual mode of migration, our model predicts that the collective invasion requires lesser ECM degradation than single cell invasion, with dynamic re-arrangements occurring in groups of collectively moving cells
Our study demonstrates the importance of ECM density and organization in fostering collective invasion through both proteolytic and non-proteolytic mechanisms
Summary
We probe the contributions of cell–cell adhesion, MMP dynamics, ECM density and organization on the mode of cancer cell invasion, and attempt to address the issue of cell invasion plasticity[13,30]. Our computational framework uses CPM-based formalism to model a cell aggregate positioned at the centre of an ECM lattice of given density and organization. Pre-existing gaps and spaces created by ECM degradation allow for movement of cells within the lattice Using this formulation we found that the overall speed and pattern of cell invasion depended greatly on cell–cell adhesiveness and MMP secretion rates. Our results suggest that the interplay between cell–cell adhesion, MMP secretion rate and ECM organization, which can be thought of as intrinsic tuning parameters of cancer cells, can lead to plasticity in cancer cell invasion
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