Targeting BACE to remodel tumor microenvironment and enhance chemo-sensitivity in metastatic melanoma

By exploring human biopsies from melanoma patients, we found the presence of protein aggregates specifically spread in metastasis compared to primitive lesions. Secretome analysis of metastatic melanoma cell lines revealed the release of amyloidogenic proteins as PMEL, APLP2, APLP1 and APP into the extracellular space. Proteins involved in amyloid maturation as APOE, QPCT, SORT1, VLDLR and DCT were also detected, attesting the presence of an active amyloidogenic machinery. Herein, we demonstrated that BACE activity regulates aggregates production, and its inhibition affects the shedding of the amyloid related proteins. We showed that BACE sheddome regulates extracellular matrix and activates mechanosignaling i.e. by impacting on YAP nuclear localization. Moreover, BACE inhibition impairs cells proliferation and enhances sensitivity to doxorubicin. These results suggest the importance of amyloids production for tumor survival, highlighting the potential of BACE inhibitor as adjuvant melanoma treatments in the development of novel therapeutic approaches.