Amyloid aggregates accumulate in melanoma metastasis modulating YAP activity.
Vittoria MataforaFrancesco FarrisUmberto RestucciaSimone TamburriGiuseppe MartanoClara BernardelliAndrea SofiaFederica PisatiFrancesca CasagrandeLuca LazzariSilvia MarsoniEmanuela BonoldiAngela BachiPublished in: EMBO reports (2020)
Melanoma progression is generally associated with increased transcriptional activity mediated by the Yes-associated protein (YAP). Mechanical signals from the extracellular matrix are sensed by YAP, which then activates the expression of proliferative genes, promoting melanoma progression and drug resistance. Which extracellular signals induce mechanotransduction, and how this is mediated, is not completely understood. Here, using secretome analyses, we reveal the extracellular accumulation of amyloidogenic proteins, i.e. premelanosome protein (PMEL), in metastatic melanoma, together with proteins that assist amyloid maturation into fibrils. We also confirm the accumulation of amyloid-like aggregates, similar to those detected in Alzheimer disease, in metastatic cell lines, as well as in human melanoma biopsies. Mechanistically, beta-secretase 2 (BACE2) regulates the maturation of these aggregates, which in turn induce YAP activity. We also demonstrate that recombinant PMEL fibrils are sufficient to induce mechanotransduction, triggering YAP signaling. Finally, we demonstrate that BACE inhibition affects cell proliferation and increases drug sensitivity, highlighting the importance of amyloids for melanoma survival, and the use of beta-secretase inhibitors as potential therapeutic approach for metastatic melanoma.
Keyphrases
- extracellular matrix
- skin cancer
- cell proliferation
- squamous cell carcinoma
- genome wide
- endothelial cells
- poor prognosis
- gene expression
- emergency department
- small cell lung cancer
- single cell
- small molecule
- signaling pathway
- binding protein
- dna methylation
- oxidative stress
- cell cycle
- mild cognitive impairment
- drug induced
- long non coding rna
- single molecule
- sensitive detection
- heat shock