About
Since its establishment in 2013, the Mechanobiology of Disease group (MBD) focuses on understanding how mechanical cues from the extracellular environment translate into cellular signals, and how this response can be leveraged in therapy.
Hippo-YAP1 Axis
Hippo pathway and its effector YAP1 are one of the main mechanosensing pathways impacting a range of phenomena: stem cell specification, proliferation, cancer progression, fibrosis, and heart regeneration among others.
ECM, Cytoskeleton, and Fibrosis
For this reasons, over the years the group has studied cell-ECM interaction mediated by YAP1 activity, the effects of YAP1 on cytoskeleton dynamics, and stem cell specification using micropatterned surfaces and atom force microscopy. Thanks to the collaboration with hospitals and medical doctors we have been exploring how changes in heart ECM composition, alignment and stiffness during heart failure affect fibroblasts’ biology. Advanced in vitro-derived ECM and disease models have been applied to unveil relationship between impaired mechanosignalling and fibroblast biology.
Cardiomyocyte Mechanosensing
While fibroblasts are able to proliferate, cardiomyocytes fail to replace the damaged tissue after injury. We observed that the ectopic Hippo-YAP1 axis activation improves regeneration through cardiomyocyte proliferation, but also leads to profound changes in cardiomyocyte myofibrilogenesis and contractile force development. We use in vitro prepared ECM, mechanically actuated 2D models and EHT 3D models to study the effects of impaired mechanosignalling on sarcomere structure, electrophysiology, and force development.
Mechano-regulated Alternative Splicing
Additionally, we have explored the expression of alternative splicing variants of YAP1 protein in different tissues. Having demonstrated that localization of mRNA splicing machinery is regulated by mechanosignalling in vitro and is associated with heart failure phenotype in cardiomyocytes in vivo, we had since thoroughly characterize the connection between mechanosignalling and alternative RNA splicing in stem cells and differentiated cell populations.
Cancer and Nanomedicine
Changes in ECM properties and composition are regarded as hallmark in cancer development and progression. These changes occurring initially at the tumor niche have profound effects on metastasis and resistance to therapy once the disease develops. By employing both cell line and patient-derived cancer organoids we aim to understand the effects of mechanosensing on cell migration, extravasation and changes in cell’s membrane composition. We combine these findings to uncover the mechanisms that drives nanoparticles’ uptake for the design of advanced nanomedicine and personalized therapies.