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Kristian Pietras

Kristian Pietras

Research team manager

Kristian Pietras

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

Author

  • Shan Wang
  • Emelie Englund
  • Pontus Kjellman
  • Zhen Li
  • Johannes Kumra Ahnlide
  • Carmen Rodriguez-Cupello
  • Mattia Saggioro
  • Ryu Kanzaki
  • Kristian Pietras
  • David Lindgren
  • Håkan Axelson
  • Christelle N. Prinz
  • Vinay Swaminathan
  • Chris D. Madsen
Show all

Summary, in English

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.

Department/s

  • Division of Translational Cancer Research
  • LUCC: Lund University Cancer Centre
  • Cancer and matrix remodelling
  • Solid State Physics
  • NanoLund: Centre for Nanoscience
  • Cell mechanobiology
  • Experimental oncology
  • Department of Laboratory Medicine
  • WCMM-Wallenberg Centre for Molecular Medicine

Publishing year

2021

Language

English

Pages

758-770

Publication/Series

Nature Cell Biology

Volume

23

Issue

7

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Cell and Molecular Biology

Status

Published

Research group

  • Cancer and matrix remodelling
  • Experimental oncology

ISBN/ISSN/Other

  • ISSN: 1465-7392