Principal Investigator, Proteomics Lab, Head of Proteomics and Metabolomics Facility, IFOM ETS-The AIRC institute of Molecular Oncology, Milan, ITALY
BACE2 orchestrates tumor-microenvironment mechanical and metabolic interactions
Host: G. Del Sal
BACE2 is an aspartic protease upregulated in several solid tumors. High BACE2 expression correlates
with worse prognosis in melanoma, glioma, colon and pancreatic cancer. Physiologically it has been
involved in the maturation and secretion of amyloidogenic targets such APP in the brain and PMEL
in melanocytes. Recently, our lab established a link between the presence of PMEL amyloid fibrils
in the metastatic melanoma secretome and YAP activation, affecting cancer proliferation and drug
sensitivity. In particular, we demonstrated that Agrin is part of the extracellular amyloid plaques,
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.
We also observed that the BACE2 sheddase activity is responsible for the tuning of both intra and
extracellular lipid content highlighting a so far unknown way adopted by cancer cells to rewire lipid
metabolism to sustain their growth.
Publications: https://pubmed.ncbi.nlm.nih.gov/?term=bachi+angela%5BAuthor%5D&sort=date
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