The YAP/TAZ transcriptional programme is not only a well-established driver of cancer progression and metastasis but also an important stimulator of tissue regeneration. Here we identified Cerebral cavernous malformations 3 (CCM3) as a regulator of mechanical cue-driven YAP/TAZ signalling, controlling both tumour progression and stem cell differentiation. We demonstrate that CCM3 localizes to focal adhesion sites in cancer-associated fibroblasts, where it regulates mechanotransduction and YAP/TAZ activation. Mechanistically, CCM3 and focal adhesion kinase (FAK) mutually compete for binding to paxillin to fine-tune FAK/Src/paxillin-driven mechanotransduction and YAP/TAZ activation. In mouse models of breast cancer, specific loss of CCM3 in cancer-associated fibroblasts leads to exacerbated tissue remodelling and force transmission to the matrix, resulting in reciprocal YAP/TAZ activation in the neighbouring tumour cells and dissemination of metastasis to distant organs. Similarly, CCM3 regulates the differentiation of mesenchymal stromal/stem cells. In conclusion, CCM3 is a gatekeeper in focal adhesions that controls mechanotransduction and YAP/TAZ signalling.

YAP/TAZ 转录程序不仅是癌症进展和转移的公认驱动因素，而且还是组织再生的重要刺激物。在这里，我们将脑海绵状血管畸形 3 (CCM3) 鉴定为机械线索驱动的 YAP/TAZ 信号转导的调节剂，控制肿瘤进展和干细胞分化。我们证明 CCM3 定位于癌症相关成纤维细胞中的粘着斑点，在那里它调节机械转导和 YAP/TAZ 激活。从机制上讲，CCM3 和粘着斑激酶 (FAK) 相互竞争结合桩蛋白以微调 FAK/Src/桩蛋白驱动的机械转导和 YAP/TAZ 激活。在乳腺癌小鼠模型中，癌症相关成纤维细胞中 CCM3 的特异性缺失导致组织重塑和力传递到基质的加剧，导致邻近肿瘤细胞中的相互 YAP/TAZ 激活和转移扩散到远处器官。同样，CCM3 调节间充质基质/干细胞的分化。总之，CCM3 是粘着斑的看门人，它控制着机械传导和 YAP/TAZ 信号。