Aging pathologies are characterized by intense remodeling of the extracellular matrix (ECM) that eventually exacerbate the progression of the disease. The role of the mechanical turmoil associated with ECM pathological remodelling in contributing to organ failure is now unequivocally recognised. Our research group has adopted numerous bioengineering tools with the goal of unveiling the molecular processes by which the cell interprets the mechanical signals arising from ECM maladaptive remodelling during the onset of pathologies. In fact, we successfully implemented the use of single cell and colony micropatterning to investigate the response of mechanically activated signalling pathways to cell constraint. Also, we adopted biocompatible hydrogels with controlled viscoelasticity and able to differentially regulate cell spreading and fate, together with uniaxial cell stretching for static and dynamic stimulation of the mechanosensitive intracellular pathways. By using these tools, we recently demonstrated the mechanical activation of Yes Associated Protein (YAP) is pivotal in reinforcing the interaction of the cell with the surrounding ECM by promoting the transcription of genes involved in focal adhesion (FA) assembly. We showed this event is relevant in breast cancer tumor progression, where malignant cells utilize the mechanical activation of the protein co-transcriptional function to increase their ability to disseminate. Also, we proved a similar mechanism exists in the failing heart, where YAP-activated cardiac fibroblasts tend to display increased contractility and worsen the disease. By using micropatterned surfaces for single cell culture, we lately unveiled a novel mechanosensitive axis which connects directly the pathological ECM remodelling with the control of RNA metabolism in vivo and in vitro.