Mutual dependence of the MRTF–SRF and YAP–TEAD pathways in cancer-associated fibroblasts is indirect and mediated by cytoskeletal dynamics

  1. Richard Treisman
  1. Signalling and Transcription Group, Francis Crick Institute, London NW1 1AT, United Kingdom
  1. Corresponding author: richard.treisman{at}crick.ac.uk
  • 1 Present address: Natoli Group, FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology Foundation (IFOM)-European Institute of Oncology (IEO) Campus, 20139 Milan, Italy

Abstract

Both the MRTF–SRF and the YAP–TEAD transcriptional regulatory networks respond to extracellular signals and mechanical stimuli. We show that the MRTF–SRF pathway is activated in cancer-associated fibroblasts (CAFs). The MRTFs are required in addition to the YAP pathway for CAF contractile and proinvasive properties. We compared MRTF–SRF and YAP–TEAD target gene sets and identified genes directly regulated by one pathway, the other, or both. Nevertheless, the two pathways exhibit mutual dependence. In CAFs, expression of direct MRTF–SRF genomic targets is also dependent on YAP–TEAD activity, and, conversely, YAP–TEAD target gene expression is also dependent on MRTF–SRF signaling. In normal fibroblasts, expression of activated MRTF derivatives activates YAP, while activated YAP derivatives activate MRTF. Cross-talk between the pathways requires recruitment of MRTF and YAP to DNA via their respective DNA-binding partners (SRF and TEAD) and is therefore indirect, arising as a consequence of activation of their target genes. In both CAFs and normal fibroblasts, we found that YAP–TEAD activity is sensitive to MRTF–SRF-induced contractility, while MRTF–SRF signaling responds to YAP–TEAD-dependent TGFβ signaling. Thus, the MRF–SRF and YAP–TEAD pathways interact indirectly through their ability to control cytoskeletal dynamics.

Keywords

Footnotes

  • Supplemental material is available for this article.

  • Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.304501.117.

  • Freely available online through the Genes & Development Open Access option.

  • Received July 10, 2017.
  • Accepted December 12, 2017.

This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.

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