European Center for Angioscience, Medicine Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, University of Heidelberg, 69120 Heidelberg, Germany.
Sci Signal. 2021 Dec 7;14(712):eabj8393. doi: 10.1126/scisignal.abj8393.
The nuclear translocation and activity of the cotranscriptional activators YAP and TAZ (YAP/TAZ) in endothelial cells (ECs) are crucial during developmental angiogenesis. Here, we studied the role of YAP/TAZ signaling in ECs in tumor angiogenesis and found that the expression of and downstream target genes in ECs correlated with tumor vascularization in human colorectal carcinomas and skin melanoma. Treatment with the YAP/TAZ inhibitor verteporfin reduced vessel density and tumor progression in a mouse colorectal cancer (CRC) model. Conditional deletion of YAP/TAZ in ECs reduced tumor angiogenesis and growth in a mouse B16-F10 melanoma model. Using cultured ECs and mice with EC-specific ablation, we showed that signal transducer and activator of transcription 3 (STAT3) was required for the activation of YAP/TAZ in tumor-associated ECs. Moreover, we showed that STAT3-mediated signaling promoted YAP/TAZ activity and that the nuclear shuttling machinery for STAT3 was also required for YAP/TAZ nuclear translocation. Together, our data highlight the role of YAP/TAZ as critical players in ECs during tumor angiogenesis and provide insight into the signaling pathways leading to their activation.
在发育性血管生成过程中，共转录激活因子 YAP 和 TAZ（YAP/TAZ）在血管内皮细胞（EC）中的核易位和活性至关重要。在这里，我们研究了 YAP/TAZ 信号在 EC 中的作用在肿瘤血管生成中，我们发现 EC 中 的表达及其下游靶基因与人类结直肠癌和皮肤黑色素瘤中的肿瘤血管化相关。YAP/TAZ 抑制剂维替泊芬的治疗降低了小鼠结直肠癌（CRC）模型中的血管密度和肿瘤进展。在小鼠 B16-F10 黑色素瘤模型中，EC 中 YAP/TAZ 的条件性缺失减少了肿瘤血管生成和生长。通过培养的 EC 和具有 EC 特异性消融的小鼠，我们表明信号转导和转录激活因子 3（STAT3）是肿瘤相关 EC 中 YAP/TAZ 激活所必需的。此外，我们表明 STAT3 介导的信号促进了 YAP/TAZ 的活性，并且 STAT3 的核穿梭机制对于 YAP/TAZ 的核易位也是必需的。总之，我们的数据强调了 YAP/TAZ 在肿瘤血管生成过程中作为 EC 中的关键参与者的作用，并深入了解了导致其激活的信号通路。
