Proteolysis and extracellular matrix remodeling as therapy-resistance mechanisms in melanoma

Drug resistance constitutes still a challenge in melanoma therapy. Despite the promising initial responses to B-RAF- and MEK-inhibitors, patients frequently acquire resistance, to single and combination therapies. A number of potential resistance mechanisms have been described, most of which bypass mutant BRAF by reactivating MAPK and Pl3K/AKT signaling. However, in addition to these autonomous changes in melanoma cells, alterations in the tumor microenvironment are thought to play an important role in the acquisition of drug resistance. The matrix components of the tumor microenvironment provide both structure and signals to the tumor cells. Nevertheless, their role in driving response to therapy and acquired resistance remains little explored. The overall aim of this project is to understand how cellular communication between melanoma cells and fibroblasts contributes to the modulation of the microenvironment to resist to therapy, thus providing new paradigms to overcome drug resistance in melanoma and design improved therapies with more durable responses.