TY - JOUR
T1 - CCM3 is a gatekeeper in focal adhesions regulating mechanotransduction and YAP/TAZ signalling
AU - Wang, Shan
AU - Englund, Emelie
AU - Kjellman, Pontus
AU - Li, Zhen
AU - Ahnlide, Johannes Kumra
AU - Rodriguez-Cupello, Carmen
AU - Saggioro, Mattia
AU - Kanzaki, Ryu
AU - Pietras, Kristian
AU - Lindgren, David
AU - Axelson, Håkan
AU - Prinz, Christelle N.
AU - Swaminathan, Vinay
AU - Madsen, Chris D.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
U2 - 10.1038/s41556-021-00702-0
DO - 10.1038/s41556-021-00702-0
M3 - Article
C2 - 34226698
AN - SCOPUS:85109904891
SN - 1465-7392
VL - 23
SP - 758
EP - 770
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 7
ER -