Scientists shed light on how cells respond to forces
The question of how single cells respond to mechanical forces, especially because such forces impact cell behaviour, has always piqued the interest of scientists. But no solution had yet to emerge... until now. A research team has succeeded in identifying two key molecules that regulate the cellular adaption to force. The study was funded in part by the RHOMECHANOVASC ('Regulation of Rho proteins by mechanical forces in the vascular system') project, which has clinched a Marie Curie Outgoing International Fellowship grant worth more than EUR 212 000 under the EU's Seventh Framework Programme (FP7).
Presented in the journal Nature Cell Biology, the findings reveal how exerting mechanical force on cells activates Rho GEF proteins through distinct signalling pathways. The team, made up of biologists and physicists and led by the University of North Carolina (UNC) at Chapel Hill in the United States, says the Rho GEFs activate Rho proteins that make up the RAS superfamily, which is a class of proteins associated with cancer activity.
The scientists say they first applied magnetic particles to cells and then used magnets to exert force on the cells. Doing this helped them generate extracellular tension.
'GEF-H1 has been shown to be regulated by microtubule binding, coupling microtubule depolymerisation with RhoA activation in multiple cellular processes, such as endothelial barrier permeability, migration and dendritic spine morphology,' the authors write in the paper. 'To test whether GEF-H1 activation could result from microtubule depolymerisation, we pretreated cells with taxol and analysed GEF-H1 activity using the nucleotide-free RhoA-pulldown assay after the application of force. We found that taxol did not affect GEF-H1 activation by force. This result indicates that GEF-H1 is activated independently of microtubule dissociation and is consistent with previous work that showed that treatment with taxol does not affect RhoA-dependent stress fibre formation in response to stretch.'
Commenting on the results of the study, UNC's Professor Keith Burridge and a senior author of the study says: 'This experiment was only possible because we were able to bring together a team of physicists and cell biologists. It's very exciting because we have identified the entire pathway between the tension exerted on the cell to proteins that, in turn, activate other proteins that we know tend to be hyperactive in cancer.'
Past studies compelled some researchers to believe that cell growth and properties are impacted by the mechanical environment of cells. Solid tumour cells, for instance, are likely to have an altered surface. And others found that the prognosis got worse if the cell matrix became stiffer.
Scientists have discovered that rigid tumours shed an increased number of cells that flee the original tumour site and could raise the risk of cancer spreading through metastasis.
'There has been a hypothesis that cell stiffness and tension create a vicious cycle leading to enhanced growth, more cell density, more tension, and larger tumours,' Professor Burridge points out. 'Innovation funding from the University Cancer Research Fund allowed us to identify the pathway and provided data that resulted in a grant renewal worth approximately USD 1.3 million [around EUR 911 000] over the next 4 years.'