β-catenin is a multifunctional protein that plays crucial roles in embryonic development, physiological homeostasis, and a wide variety of human cancers. Previously, we showed that in vivo targeted ablation of β-catenin in melanoma-associated fibroblasts after melanoma formation significantly suppressed tumor growth. However, when the expression of β-catenin was ablated in melanoma-associated fibroblasts before tumor initiation, melanoma development was surprisingly accelerated. How stromal β-catenin deficiency leads to opposite biological effects in melanoma progression is not completely understood. Here, we report that β-catenin is indispensable for the activation of primary human stromal fibroblasts and the mediation of fibroblast-melanoma cell interactions. Using coimmunoprecipitation and proximity ligation assays, we identified Yes-associated protein (YAP) as an important β-catenin-interacting partner in stromal fibroblasts. YAP is highly expressed in the nuclei of cancer-associated fibroblasts (CAFs) in both human and murine melanomas. Mechanistic investigation revealed that YAP nuclear translocation is significantly modulated by Wnt/β-catenin activity in fibroblasts. Blocking Wnt/β-catenin signaling in stromal fibroblasts inhibited YAP nuclear translocation. In the absence of YAP, the ability of stromal fibroblasts to remodel the extracellular matrix (ECM) was inhibited, which is consistent with the phenotype observed in cells with β-catenin deficiency. Further studies showed that the expression of ECM proteins and enzymes required for remodeling the ECM was suppressed in stromal fibroblasts after YAP ablation. Collectively, our data provide a new paradigm in which the β-catenin-YAP signaling axis regulates the activation and tumor-promoting function of stromal fibroblasts.

中文翻译：

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β-连环蛋白/YAP 信号轴是黑色素瘤相关成纤维细胞的关键调节因子。

β-连环蛋白是一种多功能蛋白质，在胚胎发育、生理稳态和多种人类癌症中发挥着至关重要的作用。此前，我们发现，在黑色素瘤形成后，体内靶向消除黑色素瘤相关成纤维细胞中的β-连环蛋白可显着抑制肿瘤生长。然而，当黑色素瘤相关成纤维细胞中β-连环蛋白的表达在肿瘤发生前被消除时，黑色素瘤的发展却出人意料地加速。基质β-连环蛋白缺乏如何在黑色素瘤进展中导致相反的生物学效应尚不完全清楚。在这里，我们报道β-连环蛋白对于原代人基质成纤维细胞的激活和成纤维细胞-黑色素瘤细胞相互作用的介导是不可或缺的。使用免疫共沉淀和邻近连接测定，我们确定 Yes 相关蛋白 (YAP) 是基质成纤维细胞中重要的 β-连环蛋白相互作用伙伴。YAP 在人类和小鼠黑色素瘤的癌症相关成纤维细胞 (CAF) 的细胞核中高度表达。机制研究表明，YAP 核转位受到成纤维细胞中 Wnt/β-catenin 活性的显着调节。阻断基质成纤维细胞中的 Wnt/β-catenin 信号传导可抑制 YAP 核转位。在缺乏 YAP 的情况下，基质成纤维细胞重塑细胞外基质 (ECM) 的能力受到抑制，这与在 β-连环蛋白缺乏的细胞中观察到的表型一致。进一步的研究表明，YAP 消融后，基质成纤维细胞中 ECM 蛋白和重塑 ECM 所需酶的表达受到抑制。总的来说，我们的数据提供了一个新的范例，其中 β-连环蛋白-YAP 信号轴调节基质成纤维细胞的激活和肿瘤促进功能。