Abstract
Epithelial-to-mesenchymal transition (EMT) is crucial for melanoma cells to escape keratinocyte control, invade underlying dermal tissues, and metastasize to distant organs. The hallmark of 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 unknown. Here, we show that upon Yes-associated protein 1 (YAP1) ablation in cancer-associated fibroblasts (CAFs), the progression of a BRAF-mutant mouse melanoma was significantly suppressed in vivo, and overexpressing YAP1 in CAFs accelerated melanoma growth. CAFs require the YAP1 function to proliferate, migrate, remodel the cytoskeletal machinery and matrix, and promote cancer cell invasion. By RNA-Seq, N-cadherin was identified as a major downstream effector of YAP1 signaling in CAFs. YAP1 silencing led to N-cadherin downregulation in CAFs, which subsequently induced the downregulation of N-cadherin in neighboring melanoma cells. N-cadherin downregulation inhibited the PI3K-AKT signaling pathway in melanoma cells and suppressed melanoma growth in vivo, supporting the role of N-cadherin as an adhesive and signaling molecule in melanoma cells. This finding suggests 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. Importantly, our data underscore that CAFs can regulate N-cadherin-mediated interactions with melanoma cells. Thus, disentangling cadherin-mediated cell-cell interactions can potentially disrupt tumor-stroma interactions and reverse the tumor cell invasive phenotype.