Session: Parallel session 10 - Health and biological sciences

Proteomics and lipidomics unveil BACE2 orchestration of tumor-microenvironment mechanical and metabolic interactions

BACE2 is an aspartic protease upregulated in several solid tumors. High BACE2 expression correlates with worse prognosis in melanoma, glioma, colon and pancreatic cancer (1). The secretome analysis of high BACE2 cancer cell lines revealed the production of amyloid fibrils in the metastatic melanoma secretome (2). In particular, we demonstrated that Agrin interacts with PMEL amyloid fibrils and is necessary to drive PMEL dependent YAP activation. We further characterized the signaling cascade triggered by amyloids identifying its dependency of the Hippo pathway core kinase LATS1. Further, we demonstrated that the presence of amyloid fibrils in the extracellular space enhances the migration and invasion capacity not only of melanoma cells but also in pancreatic ductal adenocarcinoma cells, suggesting a conserved mechanism adopted by cancer cells to tame the tumor microenvironment (3).

From global lipidomic profiles of melanoma cell lines using an in-house optimized LC-MS method, Opti-nQL (4), we also observed that the BACE2 activity is responsible for the tuning of both intra and extracellular lipid content. As BACE2 is a sheddase, we focused on its specific role and, by measuring spatially distributed proteomics changes, we discovered that BACE2 regulates the level and function of lipids transporters on the plasma membrane. These new targets were also validated by N-TAILS analysis. Our results highlight a previously unknown mechanism by which cancer cells rewire lipid metabolism to sustain their growth.