CCM3 is a gatekeeper in focal adhesions regulating mechanotransduction and YAP/TAZ signalling
(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.
(Less)
- author
- organization
-
- Division of Translational Cancer Research
- LUCC: Lund University Cancer Centre
- Cancer and matrix remodelling (research group)
- Solid State Physics
- NanoLund: Centre for Nanoscience
- Cell mechanobiology
- Experimental oncology (research group)
- Department of Laboratory Medicine
- WCMM-Wallenberg Centre for Molecular Medicine
- publishing date
- 2021
- 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
- 2024-09-08 07:17:56
@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}}, }