AMYLOID FIBRILS INDUCE GLYCOCALYX MEDIATED MECHANOTRANSDUCTION IN MELANOMA

PMEL is an amyloidogenic protein found overexpressed in melanoma compared to healthy skin. PMEL expression correlates with unfavorable prognosis, but the mechanism beyond the adverse disease outcome is still unknown. Recently, our lab established a link between the presence of PMEL amyloid fibrils in the metastatic melanoma secretome and YAP activation, driving cancer proliferation and drug resistance. In this study, we show that PMEL amyloid fibrils, secreted by cancer cells, are component of the extracellular matrix and modify its stiffness thus activating mechanosignalling. We highlight the signaling pathway that connects PMEL fibrils to YAP activation. In particular, we show that Agrin is part of the extracellular amyloid plaques, interacts with PMEL amyloid fibrils and it is necessary to drive PMEL dependent YAP activation. To further dissect the signaling cascade triggered by amyloids we also overexpressed LATS1 or/and LATS2, key members of Hippo pathway downstream of Agrin. The overexpression of LATS2 does not affect YAP activation, while LATS1 overexpression abrogates PMEL dependent YAP activation indicating that this kinase is a downstream inhibitor of the amyloid mediated mechano-response. We demonstrate that PMEL amyloid fibrils activate YAP in a ROCK independent fashion. Finally, we demonstrated that the presence of amyloid fibrils in the extracellular space enhances the migration and invasion capacity of melanoma cells. Our study uncovers the mechanism by which amyloid fibrils drive YAP activation impacting on migration and invasion of melanoma cells. These data suggest that inhibitors capable to reduce the formation of extracellular amyloid fibrils could interfere with melanoma progression.