Spontaneous migration of cancer cells under conditions of mechanical confinement

Abstract

When cancer cells spread away from the primary tumor, they often follow the trajectories of lymphatic vessels, nerves, white matter tracts, or other heterogeneous structures in tissues. To better understand this form of guided cell migration we designed a series of microfluidic devices that mechanically constrain migrating cancer cells inside microchannels with cross-section comparable to cell size. We observed unexpectedly fast and persistent movement in one direction for several hours of cancer cells of different types. The persistent motility occurs spontaneously, in the absence of external gradients, suggesting the presence of intrinsic mechanisms driving cancer cell motility that are induced in conditions of mechanical confinement. To probe the mechanisms responsible for this behavior, we exposed cancer cells inside channels to drugs targeting the microtubules, and measured a significant reduction in the average migration speed. Surprisingly, a small number of cells appeared not to be affected by the treatment and displayed fast and persistent migration, comparable to the untreated cells. The new matrix-free, 3D-confined motility assay replicates critical interactions that cancer cells would normally have inside tissues, is compatible with high-content, high-throughput analysis of cellular motility at single cell level, and could provide useful insights into the biology of cancer cell migratory phenotype.

Emergence of collective modes and tri-dimensional structures from epithelial confinement

“…The linear damping term ( À av i ) accounts in an effective way for the fact that cell motion is a dissipative process and effectively endows the velocity dynamics with an exponential memory kernel on a time scale 1/a. The motion of cell i is influenced by its interaction with its neighbours as reflected by the summation sign on the right-hand side of equation (1). The sum is performed on the N i cells j that are the nearest neighbours of cell i, namely, the cells that are supposed to be in direct contact with cell i.…”

“…The potential U(r) is chosen as the sum of a repulsive short-range Gaussian potential and an attractive part acting at longer distances: Neighbours of a cell/particle need to be defined to implement equation (1). For computational simplicity, this is done as follows.…”

“…The stochastic motion of each cell arises from the noise term g i in equation (1). It is taken to be an Ornstein-Uhlenbeck process with correlation time t:…”

“…For instance, constrained cancer cells in microchannels whose section is comparable to the cell size acquire a highly migrating and persistent phenotype 1 . Surprisingly, much less work has been devoted to mesoscale confinement (that is, at the scale of a small population), despite its importance in vivo.…”

Exploitation of physical and chemical constraints for three-dimensional microtissue construction in microfluidics

“…Some other chips were developed to model cancer cell migration or metastasis: ͑i͒ tumor cells were deformed when migrating across a microchannel lined with human microvascular endothelial cells; 201 ͑ii͒ invasion of cancer cells across a 3D matrix of basement membrane extract under the gradients of epidermal growth factor; 202 and ͑iii͒ motility of cancer cells in 3D under the constrains of mechanical confinement with a matrix-free environment. 203 Stroock et al 204 described the various engineering or biological challenges and opportunities for making a biomimetic microfluidic tumor model with a focus on embedding microvasculature structures.…”