Proportional modulation of proliferation and motility under 2D compressive stress depends on mesenchymal phenotype

Tumor development is accompanied by strong physico-chemical modifications. Among them, compressive stress can emerge in both the epithelial and stromal compartments. Using a simple two-dimensional compression assay which consisted in placing an agarose weight on top of adherent cells, we studied the impact of compressive stress on cell proliferation and motility in different pancreatic cancer cell lines. We observed a proportional reduction of both proliferation and motility in all tested cell types, with genotypes displaying a more “mesenchymal” phenotype (high velocity-to-proliferation ratio) and others related to a more “epithelial” phenotype (low velocity-to-proliferation ratio). Moreover, “mesenchymal” cells seemed more sensitive to compression, a result that was further suggested by a TGF β 1 induction of epithelial-to-mesenchymal transition. Finally, we measured that the change in cell proliferation was associated with a change in intracellular macromolecular crowding, which could modulate a plethora of biochemical reactions. Our results together suggest a mechanism in which all biochemical reactions related to proliferation and motility can be modulated by a change in macromolecular crowding, itself depending on the phenotype, leading to differential sensitivity to pressure.