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Signal Transduct Target Ther. 2019 Dec 24;4:63. doi: 10.1038/s41392-019-0100-7. eCollection 2019.

The β-catenin/YAP signaling axis is a key regulator of melanoma-associated fibroblasts.

Author information

1
1Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267 USA.
2
2Division of Gastroenterology, Hepatology & Nutrition, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039 USA.
3
3Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039 USA.
4
4Department of Dermatology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267 USA.
5
5Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039 USA.
6
6Department of Pediatrics, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229-3039 USA.
7
7Institute of Research, Tokyo Medical and Dental University 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510 Japan.
8
8Burnett School of Biological Sciences, University of Central Florida, Orlando, FL 32816 USA.

Abstract

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.

KEYWORDS:

Cancer microenvironment; Cell biology

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