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.
Highlights
The interface between mechanical force and gene expression is central to our understanding of normal and transformed cell behavior (Schwartz 2010; DuFort et al 2011)
A previous analysis of stromal fibroblasts associated with tumors in the MMTV-PyMT mouse mammary carcinoma model suggested that expression of MRTF–serum response factor (SRF) target genes may be increased in Cancer-associated fibroblasts (CAFs) (Calvo et al 2013)
Consistent with this, an MRTF–SRF reporter gene exhibited increased activity in CAFs compared with normal mammary fibroblasts (NFs) (Fig. 1C) even though MRTF-A and MRTF-B expression was comparable in the two cell types (Supplemental Fig. S1A)
Summary
The interface between mechanical force and gene expression is central to our understanding of normal and transformed cell behavior (Schwartz 2010; DuFort et al 2011). Which are recruited to DNA by their partner, SRF—control expression of dozens of cytoskeletal genes, including αSMA (for review, see Olson and Nordheim 2010) They respond to Rho-GTPase signals, directly sensing changes in G-actin concentration via their regulatory RPEL domain, and accumulate in the nucleus when G-actin levels are low (Cen et al 2003; Miralles et al 2003; Vartiainen et al 2007). YAP and TAZ, which bind DNA in association with members of the TEAD family of DNA-binding cofactors, were first characterized as effectors of the Hippo growth control pathway (for review, see Meng et al 2016) They respond to Rho-GTPase signaling, accumulating in the nucleus in response to high cytoskeletal tension induced by mechanical cues (Dupont et al 2011; Wada et al 2011; Das et al 2016). We show that activation of either pathway potentiates the activity of the other indirectly and that this depends on cytoskeletal dynamics
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