Xio Yao, Zhou Lilni, Andl Thomas, Zhang Yuhang
University of Cincinnati.
Res Sq. 2023 Jul 28:rs.3.rs-2944243. doi: 10.21203/rs.3.rs-2944243/v3.
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 , 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 , 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.
上皮-间质转化（EMT）对于黑色素瘤细胞逃避角质形成细胞的控制、侵袭下方的真皮组织并转移至远处器官至关重要。EMT的标志是从上皮钙黏蛋白（E-钙黏蛋白）转变为神经钙黏蛋白（N-钙黏蛋白），这使得黑色素瘤细胞能够与基质成纤维细胞形成同型N-钙黏蛋白介导的黏附。然而，在黑色素瘤中“钙黏蛋白转换”是如何启动、维持和调控的仍不清楚。在这里，我们表明，在癌症相关成纤维细胞（CAF）中敲除Yes相关蛋白1（YAP1）后，BRAF突变型小鼠黑色素瘤的进展受到显著抑制，而在CAF中过表达YAP1则加速了黑色素瘤的生长。CAF需要YAP1的功能来增殖、迁移、重塑细胞骨架机制和基质，并促进癌细胞侵袭。通过RNA测序，N-钙黏蛋白被确定为CAF中YAP1信号的主要下游效应因子。YAP1沉默导致CAF中N-钙黏蛋白下调，随后诱导邻近黑色素瘤细胞中N-钙黏蛋白下调。N-钙黏蛋白下调抑制了黑色素瘤细胞中的PI3K-AKT信号通路并抑制了黑色素瘤生长，支持了N-钙黏蛋白作为黑色素瘤细胞中黏附分子和信号分子的作用。这一发现表明，CAF中YAP1的缺失通过黑色素瘤细胞与CAF之间N-钙黏蛋白介导的相互作用诱导黑色素瘤细胞中p-AKT信号下调。重要的是，我们的数据强调CAF可以调节与黑色素瘤细胞的N-钙黏蛋白介导的相互作用。因此，解开钙黏蛋白介导的细胞间相互作用可能会破坏肿瘤-基质相互作用并逆转肿瘤细胞的侵袭表型。
