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Experimental and modeling study of the formation of cell aggregates with differential substrate adhesion.

ABSTRACT: The study of cell aggregation in vitro has a tremendous importance these days. In cancer biology, aggregates and spheroids serve as model systems and are considered as pseudo-tumors that are more realistic than 2D cell cultures. Recently, in the context of brain tumors (gliomas), we developed a new poly(ethylene glycol) (PEG)-based hydrogel, with adhesive properties that can be controlled by the addition of poly(L-lysine) (PLL), and a stiffness close to the brain's. This substrate allows the motion of individual cells and the formation of cell aggregates (within one day), and we showed that on a non-adhesive substrate (PEG without PLL is inert for cells), the aggregates are bigger and less numerous than on an adhesive substrate (with PLL). In this article, we present new experimental results on the follow-up of the formation of aggregates on our hydrogels, from the early stages (individual cells) to the late stages (aggregate compaction), in order to compare, for two cell lines (F98 and U87), the aggregation process on the adhesive and non-adhesive substrates. We first show that a spaceless model of perikinetic aggregation can reproduce the experimental evolution of the number of aggregates, but not of the mean area of the aggregates. We thus develop a minimal off-lattice agent-based model, with a few simple rules reproducing the main processes that are at stack during aggregation. Our spatial model can reproduce very well the experimental temporal evolution of both the number of aggregates and their mean area, on adhesive and non-adhesive soft gels and for the two different cell lines. From the fit of the experimental data, we were able to infer the quantitative values of the speed of motion of each cell line, its rate of proliferation in aggregates and its ability to organize in 3D. We also found qualitative differences between the two cell lines regarding the ability of aggregates to compact. These parameters could be inferred for any cell line, and correlated with clinical properties such as aggressiveness and invasiveness.

SUBMITTER: Adenis L

PROVIDER: S-EPMC7001941 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Collective migration of cells is of fundamental importance for a number of biological functions such as tissue development and regeneration, wound healing and cancer metastasis. The movement of cell groups consisting of multiple cells connected by cell-cell junctions depends on both extracellular and intercellular contacts. Epithelial cell assemblies are thus regulated by a cross-talk between cell-substrate and cell-cell interactions. Here, we investigated the onset of collective migration in groups of cells as they expand from a few cells into large colonies as a function of extracellular matrix (ECM) protein coating. By varying the amount of ECM presented to the cells, we observe that the mode of colony expansion, as well as their overall geometry, is strongly dependent on substrate adhesiveness. On high ECM protein coated surfaces, cells at the edges of the colonies are well spread exhibiting large outward-pointing protrusive activity, whereas cellular colonies display more circular and convex shapes on less adhesive surfaces. Actin structures at the edge of the colonies also show different organizations with the formation of lamellipodial structures on highly adhesive surfaces and a pluricellular actin cable on less adhesive ones. The analysis of traction forces and cell velocities within the cellular assemblies confirm these results. By increasing ECM protein density, cells exert higher traction forces together with a higher outward motility at the edges. Furthermore, tuning cell-cell adhesion of epithelial cells modified the mode of expansion of the colonies. Finally, we used a recently developed computational model to recapitulate the emergent experimental behaviors of expanding cell colonies and extract that the main effect of the different cell-substrate interactions is on the ability of edge cells to form outward lamellipodia-driven motility. Overall, our data suggest that switching behaviors of epithelial cell assemblies result in a tug-of-war between friction forces at the cell-substrate interface and cell-cell interactions.

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Experimental and modeling study of the formation of cell aggregates with differential substrate adhesion.

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