YAP1 controls the N-cadherin-mediated tumor-stroma interaction in melanoma progression

• Published in: Oncogene 2024-03, Vol.43 (12), p.884-898
• Main Authors: Xiao, Yao, Zhou, Linli, Andl, Thomas, Zhang, Yuhang
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/1; 13/106; 13/109; 13/31; 13/44; 13/51; 13/89; 13/95; 14/19; 38/91; 45/77; 45/90; 631/67/327; 631/80/86; 64/60; Ablation; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; AKT protein; Animals; Apoptosis; Cadherins - genetics; Cadherins - metabolism; Cancer-Associated Fibroblasts - metabolism; Cell Biology; Cell interactions; Cell Line, Tumor; Cell Movement; Cell Proliferation; Down-regulation; E-cadherin; Epithelial-Mesenchymal Transition; Fibroblasts; Human Genetics; Internal Medicine; Medicine; Medicine & Public Health; Melanoma; Melanoma - pathology; Mice; N-Cadherin; Oncology; Phenotypes; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Signal transduction; Stroma; Transcription Factors - genetics; Transcription Factors - metabolism; Tumors; YAP-Signaling Proteins - metabolism; Yes-associated protein
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-024-02953-1

The hallmark of epithelial-to-mesenchymal transition (EMT) is the switch from epithelial cadherin (E-cadherin) to neural cadherin (N-cadherin), allowing melanoma cells to form a homotypic N-cadherin-mediated adhesion with stromal fibroblasts. However, how cadherin switching is initiated, maintained, and regulated in melanoma remains elusive. Here, we report a novel mechanism underlying cadherin switching in melanoma cells that is regulated by stromal Yes-associated protein 1 (YAP1) signaling. The progression of a BRAF-mutant mouse melanoma was suppressed in vivo upon YAP1 ablation in cancer-associated fibroblasts (CAFs). On the contrary, overexpressing YAP1 in CAFs accelerated melanoma development. By RNA-Seq, N-cadherin was identified as a major downstream effector of YAP1 signaling in CAFs. YAP1 silencing reduced N-cadherin expression in CAFs, leading to the downregulation of N-cadherin in neighboring melanoma cells. N-cadherin ablation inhibited the PI3K-AKT signaling pathway in melanoma cells and melanoma cell proliferation. The findings suggest that YAP1 depletion in CAFs induces the downregulation of p-AKT signaling in melanoma cells through the N-cadherin-mediated interaction between melanoma cells and CAFs. The data underscore an important role of CAFs in regulating N-cadherin-mediated adhesion and signaling in melanoma and highlight that disentangling cadherin-mediated cell-cell interactions can potentially disrupt tumor-stroma interactions and reverse the tumor cell invasive phenotype.