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

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.