CCM3 is a gatekeeper in focal adhesions regulating mechanotransduction and YAP/TAZ signalling

Wang et al. identify CCM3 as a negative regulator of YAP/TAZ activation and mechanotransduction in focal adhesions, with important roles in controlling mesenchymal/stromal stem cell differentiation and metastasis in mouse models of breast cancer. 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.

Automated summary

Wang et al. have identified CCM3 as a negative regulator of YAP/TAZ activation and mechanotransduction in focal adhesions, with crucial roles in controlling mesenchymal/stromal stem cell differentiation and metastasis. CCM3 functions as a gatekeeper in focal adhesions, regulating mechanotransduction and YAP/TAZ signaling by competing with focal adhesion kinase for binding to paxillin. Loss of CCM3 in cancer-associated fibroblasts leads to exacerbated tissue remodelling and metastasis dissemination in mouse models of breast cancer.