The Wnt/β-catenin signalling pathway controls a variety of cellular behaviours, including adhesion, proliferation and differentiation; its deregulation is often associated with cancer progression as indicated, for instance, by Wnt3a overexpression in breast cancer. The stiffness of the extracellular matrix (ECM) also affects processes similar to Wnt signalling, but it is unclear how mechanical forces from the microenvironment are integrated into biochemical pathways. In this study, Celeste Nelson and co-workers (Han et al. 2018) use engineered synthetic substrata to recapitulate the mechanical stiffness of both normal mammary tissue and breast tumours in order to investigate the effects of substrate stiffness on Wnt3a-induced cell proliferation. They find that exposure to Wnt3a increased the percentage of proliferating cells on stiff substrata, but not on soft substrata. Interestingly, this effect is not mediated by Yap/Taz, a well-known mechanosensory pathway, as its depletion does not affect cell proliferation downstream of Wnt on stiff substrata. By contrast, depletion of integrin-linked kinase (ILK) rendered cells unresponsive to Wnt3a, and ectopic expression of ILK enabled Wnt3a-induced cell proliferation on soft substrata. Mechanistically, the authors show that ILK regulates expression of the Wnt receptor frizzled-1 and so modulates downstream Wnt signalling. Taken together, the findings presented here identify for the first time a link between mechanosensing through ILK and canonical Wnt signalling.
