Cdc42EP3/BORG2 and Septin Network Enables Mechano-transduction and the Emergence of Cancer-Associated Fibroblasts

Calvo, Fernando; Ranftl, Romana; Hooper, Steven; Farrugia, Aaron J.; Moeendarbary, Emad; Bruckbauer, Andreas; Batista, Facundo D.; Charras, Guillaume; Sahai, Erik

doi:10.1016/j.celrep.2015.11.052

Cited by 118 publications

(187 citation statements)

References 41 publications

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“…S6C). Consistent with the reported dependence of Factin assembly on Cdc42EP3 levels (Calvo et al 2015), the ability of MRTF 123-1A to induce activity of the YAP-TEAD reporter and YAP-TEAD target genes in NFs was sensitive to Cdc42EP3 depletion (Fig. 7H).…”

Section: Mrtf-srf Signaling Activates Yap Through Cell Contractilitysupporting

confidence: 73%

“…8H). YAP activation in CAFs is dependent on cell adhesion and contracility (Calvo et al 2013(Calvo et al , 2015. In normal fibroblasts, MRTF-SRF signaling potentiates YAP-TEAD signaling in an adhesion-and contractilitydependent manner.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have shown that the septin regulator Cdc42EP3 is required in CAFs for F-actin assembly, contractility, and YAP activation (Calvo et al 2015). In CAFs, expression of Cdc42EP3, which is a direct MRTF-SRF target in fibroblasts (Esnault et al 2014;Gualdrini et al 2016), was elevated and MRTF-dependent (Fig.…”

Section: Mrtf-srf Signaling Activates Yap Through Cell Contractilitymentioning

confidence: 99%

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

2017

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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.

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Section: Mrtf-srf Signaling Activates Yap Through Cell Contractilitysupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Mrtf-srf Signaling Activates Yap Through Cell Contractilitymentioning

confidence: 99%

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

2017

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“…Interestingly, a recent study showed that in vivo septins are required for the remodeling of the extracellular matrix by cancer-associated fibroblasts (CAFs). In addition, septins partly promote CAF-induced tumor growth and pro-angiogenic activity (Calvo et al, 2015). This is the first evidence of septins playing a role in the organization and properties of the tumor microenvironment, which is important for the progression of cancer.…”

Section: Emerging Roles Of Septins In Cancermentioning

confidence: 99%

Septin Mutations in Human Cancers

Angelis

Spiliotis

2016

Front. Cell Dev. Biol.

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Septins are GTP-binding proteins that are evolutionarily and structurally related to the RAS oncogenes. Septin expression levels are altered in many cancers and new advances point to how abnormal septin expression may contribute to the progression of cancer. In contrast to the RAS GTPases, which are frequently mutated and actively promote tumorigenesis, little is known about the occurrence and role of septin mutations in human cancers. Here, we review septin missense mutations that are currently in the Catalog of Somatic Mutations in Cancer (COSMIC) database. The majority of septin mutations occur in tumors of the large intestine, skin, endometrium and stomach. Over 25% of the annotated mutations in SEPT2, SEPT4, and SEPT9 belong to large intestine tumors. From all septins, SEPT9 and SEPT14 exhibit the highest mutation frequencies in skin, stomach and large intestine cancers. While septin mutations occur with frequencies lower than 3%, recurring mutations in several invariant and highly conserved amino acids are found across different septin paralogs and tumor types. Interestingly, a significant number of these mutations occur in the GTP-binding pocket and septin dimerization interfaces. Future studies may determine how these somatic mutations affect septin structure and function, whether they contribute to the progression of specific cancers and if they could serve as tumor-specific biomarkers.

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“…In the case of the septin knockout mice with embryonic lethal phenotypes, podocyte-specific knockout mouse models are necessary for defining the role of these specific septins in the maintenance of glomerular ultrafiltration in higher vertebrates. A recent study revealed that septin network is required for the process of mechanotransduction (Calvo et al, 2015). Mechanical stimuli, including stretch, affect podocyte biology in vitro and play a significant role in the development of glomerulosclerosis in vivo (Schordan et al, 2013).…”

Section: Discussionmentioning

confidence: 99%