Amyloid aggregates accumulate in melanoma metastasis modulating YAP activity

• Published in: EMBO reports Vol. 21; no. 9; pp. e50446 - n/a
• Main Authors: Matafora, Vittoria, Farris, Francesco, Restuccia, Umberto, Tamburri, Simone, Martano, Giuseppe, Bernardelli, Clara, Sofia, Andrea, Pisati, Federica, Casagrande, Francesca, Lazzari, Luca, Marsoni, Silvia, Bonoldi, Emanuela, Bachi, Angela
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03-09-2020; Blackwell Publishing Ltd; John Wiley and Sons Inc
• Subjects: Accumulation; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Aggregates; Alzheimer's disease; amyloid; Amyloidogenesis; Amyloidogenic Proteins; BACE2; Cell growth; Cell lines; Cell proliferation; Drug resistance; EMBO03; EMBO24; EMBO37; Extracellular matrix; Fibrils; Gene expression; Humans; Kinases; Localization; Maturation; Mechanical stimuli; mechanosignaling; Mechanotransduction; Mechanotransduction, Cellular; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Metastases; Metastasis; Neurodegenerative diseases; Proteins; Secretase; Secretome; Transcription; Transcription Factors - genetics; Transcription Factors - metabolism; Yes-associated protein; β-Site APP-cleaving enzyme 2; β-Site APP-cleaving enzymes; BACE2; amyloid; secretome; metastasis; mechanosignaling
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.202050446

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.
Synopsis
The accumulation of PMEL fibrils in the metastatic melanoma microenvironment modulates YAP activity. Preventing aggregate formation reduces metastatic cell proliferation and chemosensitivity, suggesting beta‐secretase inhibition as treatment for metastatic melanoma.
Amyloid aggregates are enriched in the secretome of metastatic compared to primary melanoma.
Amyloid aggregates induce nuclear localization of YAP and its transcriptional activity.
Amyloid impairment through BACE2 inhibition affects metastatic cell proliferation and chemosensitivity.
Graphical Abstract
The accumulation of PMEL fibrils in the metastatic melanoma microenvironment modulates YAP activity. Preventing aggregate formation reduces metastatic cell proliferation and chemosensitivity, suggesting beta‐secretase inhibition as treatment for metastatic melanoma.