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.

中文翻译：

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淀粉样蛋白聚集体在黑色素瘤转移中积累，调节 YAP 活性。


黑色素瘤的进展通常与 Yes 相关蛋白 (YAP) 介导的转录活性增加有关。 YAP 感知来自细胞外基质的机械信号，然后激活增殖基因的表达，促进黑色素瘤进展和耐药性。哪些细胞外信号诱导机械转导，以及这是如何介导的，尚不完全清楚。在这里，利用分泌组分析，我们揭示了转移性黑色素瘤中淀粉样蛋白（即前黑素体蛋白（PMEL））的细胞外积累，以及协助淀粉样蛋白成熟为原纤维的蛋白质。我们还证实了淀粉样蛋白样聚集物的积累，类似于在阿尔茨海默病、转移细胞系以及人类黑色素瘤活检中检测到的情况。从机制上讲，β-分泌酶 2 (BACE2) 调节这些聚集体的成熟，进而诱导 YAP 活性。我们还证明重组 PMEL 原纤维足以诱导机械转导，触发 YAP 信号传导。最后，我们证明 BACE 抑制会影响细胞增殖并增加药物敏感性，强调淀粉样蛋白对于黑色素瘤存活的重要性，以及使用 β 分泌酶抑制剂作为转移性黑色素瘤的潜在治疗方法。