Impact of Tumor Cell Cytoskeleton Organization on Invasiveness and Migration: A Microchannel-Based Approach

Abstract

Cell migration is a fundamental feature of the interaction of cells with their surrounding. The cell's stiffness and ability to deform itself are two major characteristics that rule migration behavior especially in three-dimensional tissue. We simulate this situation making use of a micro-fabricated migration chip to test the active invasive behavior of pancreatic cancer cells (Panc-1) into narrow channels. At a channel width of 7 µm cell migration through the channels was significantly impeded due to size exclusion. A striking increase in cell invasiveness was observed once the cells were treated with the bioactive lipid sphingosylphosphorylcholine (SPC) that leads to a reorganization of the cell's keratin network, an enhancement of the cell's deformability, and also an increase in the cell's migration speed on flat surfaces. The migration speed of the highly deformed cells inside the channels was three times higher than of cells on flat substrates but was not affected upon SPC treatment. Cells inside the channels migrated predominantly by smooth sliding while maintaining constant cell length. In contrast, cells on adhesion mediating narrow lines moved in a stepwise way, characterized by fluctuations in cell length. Taken together, with our migration chip we demonstrate that the dimensionality of the environment strongly affects the migration phenotype and we suggest that the spatial cytoskeletal keratin organization correlates with the tumor cell's invasive potential.

A Hybrid Model Describing Different Morphologies of Tumor Invasion Fronts

“…8(B). Indeed, we can conclude that the ability of tumor cells to undergo continuous and dramatic changes in their morphology during motion has a big impact on the aggressiveness of the disease, as also provided in [58]. A therapeutic approach that targets the dynamics of polarization/depolarization of the cytoskeletal of cancer cells, as the use of phalloidin-like compounds, may be therefore potentially effective.…”

A computational mechanics approach to assess the link between cell morphology and forces during confined migration

“…3, the total displacement of the frontal edge of the cell is reported for the four simulations. Then, as previously proposed by (Rolli et al 2010;, we can classify the cell as permeative, invasive or penetrating. The permeative behaviour is observable for channel 16 and channel 12 (Fig.…”

“…Active gel layers submitted to external forces have been used to represent acto-myosin cells migrating in a free or confined (Hawkins et al 2009;Hawkins and Voituriez 2010) environment. Scianna and Preziosi have presented a cellular potts model (CPM), which reproduces an experimental assay very similar to those used in (Taylor et al 2005;Irimia et al 2007;Faure-André et al 2008;Irimia and Toner 2009;Rolli et al 2010;Heuzé et al 2011). In this model, the cell is modelled as a discrete physical unit, including the cytosol and the nucleus, while channels of different widths constitute the migration chamber.…”

Evaluation of Cancer Stem Cell Migration Using Compartmentalizing Microfluidic Devices and Live Cell Imaging

“…Due to a limitation in visual inspection and geometrical manipulation, conventional migration assays 5 are restricted to quantifying overall cell populations. In contrast, microfluidic devices permit single cell analysis because of compatibility with modern microscopy and control over microenvironment [6][7][8][9] .…”

“…Due to a limitation in visual inspection and geometrical manipulation, conventional migration assays 5 are restricted to quantifying overall cell populations. In contrast, microfluidic devices permit single cell analysis because of compatibility with modern microscopy and control over microenvironment [6][7][8][9] .We present a method for detailed characterization of BTSC migration using compartmentalizing microfluidic devices. These PDMS-made devices cast the tissue culture environment into three connected compartments: seeding chamber, receiving chamber and bridging microchannels.…”