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

Wang, Shan LU ; Englund, Emelie LU ; Kjellman, Pontus LU ; Li, Zhen LU ; Ahnlide, Johannes Kumra LU orcid ; Rodriguez-Cupello, Carmen LU orcid ; Saggioro, Mattia LU ; Kanzaki, Ryu LU orcid ; Pietras, Kristian LU orcid and Lindgren, David LU , et al. (2021) In Nature Cell Biology 23(7). p.758-770
Abstract

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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Cell Biology
volume
23
issue
7
pages
13 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:34226698
  • scopus:85109904891
ISSN
1465-7392
DOI
10.1038/s41556-021-00702-0
language
English
LU publication?
yes
id
36a4751e-9a68-42a7-8200-ce640ca5fe7a
date added to LUP
2021-12-23 13:54:08
date last changed
2024-06-15 23:15:53
@article{36a4751e-9a68-42a7-8200-ce640ca5fe7a,
  abstract     = {{<p>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.</p>}},
  author       = {{Wang, Shan and Englund, Emelie and Kjellman, Pontus and Li, Zhen and Ahnlide, Johannes Kumra and Rodriguez-Cupello, Carmen and Saggioro, Mattia and Kanzaki, Ryu and Pietras, Kristian and Lindgren, David and Axelson, Håkan and Prinz, Christelle N. and Swaminathan, Vinay and Madsen, Chris D.}},
  issn         = {{1465-7392}},
  language     = {{eng}},
  number       = {{7}},
  pages        = {{758--770}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Cell Biology}},
  title        = {{CCM3 is a gatekeeper in focal adhesions regulating mechanotransduction and YAP/TAZ signalling}},
  url          = {{http://dx.doi.org/10.1038/s41556-021-00702-0}},
  doi          = {{10.1038/s41556-021-00702-0}},
  volume       = {{23}},
  year         = {{2021}},
}