Contact Guidance Drives Upward Cellular Migration at the Mesoscopic Scale

Introduction Cancer metastasis is associated with increased cancer incidence, recurrence, and mortality. The role of cell contact guidance behaviors in cancer metastasis has been recognized but has not been elucidated yet.Methods The contact guidance behavior of cancer cells in response to topographical constraints is identified using microgrooved substrates with varying dimensions at the mesoscopic scale. Then, the cell morphology is determined to quantitatively analyze the effects of substrate dimensions on cells contact guidance. Cell density and migrate velocity signatures within the cellular population are determined using time-lapse phase-contrast microscopy. The effect of soluble factors concentration is determined by culturing cells upside down. Then, the effect of cell-substrate interaction on cell migration is investigated using traction force microscopy.Results With increasing depth and decreasing groove width, cell elongation and alignment are enhanced, while cell spreading is inhibited. Moreover, cells display preferential distribution on the ridges, which is found to be more pronounced with increasing depth and groove width. Determinations of cell density and migration velocity signatures reveal that the preferential distribution on ridges is caused by cell upward migration. Combined with traction force measurement, we find that migration toward ridges is governed by different cell-substrate interactions between grooves and ridges caused by geometrical constraints. Interestingly, the upward migration of cells at the mesoscopic scale is driven by entropic maximization.Conclusions The mesoscopic cell contact guidance mechanism based on the entropic force driven theory provides basic support for the study of cell alignment and migration along healthy tissues with varying size, thereby aiding in the prediction of cancer metastasis.