Breaking the Mechanical Compass: Disrupting Durotaxis to Halt Fibrosis and Metastasis

Abstract

Durotaxis is the directed migration of cells along tissue stiffness gradients, and is emerging as a fundamental mechanobiological process orchestrating progression in diseases such as fibrosis and cancer. Despite compelling in vitro evidence demonstrating durotactic behaviour across multiple cell types, translating these findings to in vivo contexts has remained challenging due to the inherent complexity of isolating biomechanical cues from the myriad biochemical and architectural features that collectively define tissue properties. In their recent Nature Cell Biology study, Al-Hilal and colleagues address this translational gap through innovative bioengineering approaches combined with genetic models. Using high-resolution atomic force microscopy and intravital two-photon imaging, the authors demonstrate that pathological stiffness gradients drive fibroblast recruitment and activation in bleomycin-induced lung fibrosis, whilst simultaneously promoting quasi-mesenchymal pancreatic cancer cell dissemination. Critically, they identify the FAK-paxillin signalling axis as the mechanosensory machinery underpinning durotactic behaviour in both contexts. Pharmacological inhibition of this pathway using JP-153, or genetic disruption of tumour cell durotaxis, significantly attenuates fibrosis and metastatic burden without affecting primary tumour growth. These findings establish durotaxis as a therapeutically tractable mechanism in fibrotic and neoplastic disease, introducing a paradigm shift whereby targeting biomechanical sensing pathways may offer precise therapeutic intervention whilst preserving developmental and homeostatic processes dependent on functional mechanosensing.