The role of ECM mechanics in cancer mechanotransduction through unraveling the molecular machinery of integrins, FAK, and YAP signaling

Mechanotransduction, the process by which cells convert mechanical stimuli into biochemical signals, is fundamental for maintaining tissue homeostasis and regulating physiological functions. The extracellular matrix (ECM) serves as a critical mediator of mechanotransduction, with its mechanical properties influencing cellular behaviour and function through complex molecular machinery. This comprehensive review examines the role of ECM mechanics in disease mechanotransduction, focusing on the molecular machinery of integrins, focal adhesion kinase (FAK) and YAP signaling pathways. We explore the structure and composition of the ECM, including detailed analysis of key components such as collagens, elastin, glycoproteins, proteoglycans, hyaluronic acid and matrix metalloproteinases. The review elucidates how integrins function as key mediators of mechanotransduction, the role of FAK in signal transduction, and the mechanosensitive functions of YAP/TAZ signaling. We examine the intricate crosstalk between these mechanotransduction pathways and their dysregulation in cancer. Finally, we discuss emerging therapeutic strategies targeting mechanotransduction pathways and the challenges and opportunities for translating mechanotransduction research into clinical interventions. Understanding these complex mechanotransduction networks is crucial for developing novel therapeutic approaches to treat diseases characterized by altered tissue mechanics and dysregulated cellular responses to mechanical cues.