For every action there is an equal and opposite reaction — if you push a wall it pushes back with the same force. So, does it follow that in tumours, which are more rigid than normal tissues, cells are under more tensional stress than their normal counterparts owing to the force that is exerted by the surrounding matrix? New findings from Valerie Weaver's group show this to be the case, and because of this tumour cells have an increased activation of growth factor signalling pathways, which promotes their malignant phenotype.

Tumours are often identified as a hard mass within a normal tissue — a characteristic that is exploited for breast cancer screening. But the molecular relationship between tissue rigidity and tumour behaviour is not clear. To address this, Valerie Weaver and colleagues analysed non-malignant human mammary epithelial cells grown in three-dimensional gels of a defined rigidity. Cells grown in gels with a comparable stiffness to normal mammary tissue produced mammary acini as expected, with polarized cells and evident adherens junctions between the cells. However, when these cells were plated out on gels of increasing rigidity they lost the capacity to form these structures and demonstrated increased growth, similar to malignant breast cancer cells plated out in a normal 3D matrix.

What then, in molecular terms, changes in cells that are subjected to an increased exogenous force? Weaver and colleagues found that although cells adhered with the same force to all the gels that were analysed regardless of their rigidity, the nature of the adhesion complexes differed. Integrins that are expressed at the points of cellular adhesion to an underlying matrix function as mechanotransductors, relating the nature and force of the matrix interaction to intracellular signalling pathways. Integrin adhesions formed in fibroblasts that were plated out on all types of gels, but only in the stiffer gels did these adhesions result in the induction of focal adhesions with the recruitment and activation of both focal adhesion kinase (FAK) and vinculin. It was only in the cells with focal adhesions that increased activation of the extracellular regulated kinase (ERK) signalling pathway was seen. Moreover, because integrins were activated by a stiffer matrix, levels of Rho GTPase activity and its downstream effector Rho-associated, coiled-coil containing protein kinase 1 (ROCK1) were increased, which in turn further increased focal adhesion formation, cytoskeletal tension, cell spreading and cell growth.

Why are the links between Newton's third law and signalling pathways of interest to tumour biologists? Changes in the nature of the matrix are known to occur early on in tumour development. So, a greater understanding of how exogenous force and cytoskeletal tension are integrated and how they influence integrin adhesions and activation of ERK offers a fresh perspective on the molecular basis of tumour formation.