Abstract
The ability of cancer cells to sense external mechanical forces has emerged as a significant factor in the promotion of cancer invasion. Currently there are conflicting reports in the literature with regard to whether glioblastoma (GBM) brain cancer cell migration and invasion is rigidity-sensitive. In order to address this question we have compared the rigidity-response of primary patient-derived GBM lines. Cells were plated on polyacrylamide gels of defined rigidity that reflect the diversity of the brain tissue mechanical environment, and cell morphology and migration were analysed by time-lapse microscopy. Invasiveness was assessed in multicellular spheroids embedded in 3D matrigel cultures. Our data reveal a range of rigidity-dependent responses between the patient-derived cell lines, from reduced migration on the most compliant tissue stiffness to those that are insensitive to substrate rigidity and are equally migratory irrespective of the underlying substrate stiffness. Notably, the rigidity-insensitive GBM cells show the greatest invasive capacity in soft 3D matrigel cultures. Collectively our data confirm both rigidity-dependent and independent behaviour in primary GBM patient-derived cells.
Highlights
8.0 versus 50). (C) Adhesion of the indicated cell lines to laminin-coated wells
Assessment of mitotic events throughout the timelapse period revealed that there were no significant differences between the cell lines (Supplementary Figure 2)
Quantification of cell shapes confirmed that JK2 and WK1 cells progressively lost their rounded phenotypes as the matrix rigidity increased, RN1 and PR1 spreading peaked at 8.0 kPa and 1.0 kPa, respectively, and the shape of SJH1 cells was unaffected (Fig. 1B)
Summary
8.0 versus 50). (C) Adhesion of the indicated cell lines to laminin-coated wells. Values shown are the A570 and represent the average of 3 individual repeats. There was no significant difference in adhesion to laminin between the three cell lines, (p = 0.134) one-way ANOVA. Mechanical heterogeneity is important in the regulation of normal brain biology[22,23,24,25] and may influence tumour cells as they invade different brain regions. In response to external mechanical forces, cells exert increasing Rho-GTPase dependent contractile force through their acto-myosin cytoskeleton[6]. This leads to greater traction forces on the surrounding extracellular matrix (ECM) and enhanced migration and invasion. In the present study we reveal diverse rigidity-dependent responses in primary GBM lines
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