A paracrine activin A–mDia2 axis promotes squamous carcinogenesis via fibroblast reprogramming
Abstract Cancer‐associated fibroblasts (CAFs) are key regulators of tumorigenesis and promising targets for next‐generation therapies. We discovered that cancer cell‐derived activin A reprograms fibroblasts into pro‐tumorigenic CAFs. Mechanistically, this occurs via Smad2‐mediated transcriptional re...
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| Format: | Article |
| Language: | English |
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Springer Nature
2020-03-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201911466 |
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| author | Michael Cangkrama Mateusz Wietecha Nicolas Mathis Rin Okumura Luca Ferrarese Dunja Al‐Nuaimi Maria Antsiferova Reinhard Dummer Metello Innocenti Sabine Werner |
| author_facet | Michael Cangkrama Mateusz Wietecha Nicolas Mathis Rin Okumura Luca Ferrarese Dunja Al‐Nuaimi Maria Antsiferova Reinhard Dummer Metello Innocenti Sabine Werner |
| author_sort | Michael Cangkrama |
| collection | DOAJ |
| description | Abstract Cancer‐associated fibroblasts (CAFs) are key regulators of tumorigenesis and promising targets for next‐generation therapies. We discovered that cancer cell‐derived activin A reprograms fibroblasts into pro‐tumorigenic CAFs. Mechanistically, this occurs via Smad2‐mediated transcriptional regulation of the formin mDia2, which directly promotes filopodia formation and cell migration. mDia2 also induces expression of CAF marker genes through prevention of p53 nuclear accumulation, resulting in the production of a pro‐tumorigenic matrisome and secretome. The translational relevance of this finding is reflected by activin A overexpression in tumor cells and of mDia2 in the stroma of skin cancer and other malignancies and the correlation of high activin A/mDia2 levels with poor patient survival. Blockade of this signaling axis using inhibitors of activin, activin receptors, or mDia2 suppressed cancer cell malignancy and squamous carcinogenesis in 3D organotypic cultures, ex vivo, and in vivo, providing a rationale for pharmacological inhibition of activin A‐mDia2 signaling in stratified cancer patients. |
| format | Article |
| id | doaj-art-7e9880af155f4dfe920e625f78f674f9 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2020-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-7e9880af155f4dfe920e625f78f674f92025-08-24T11:44:13ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-03-0112412110.15252/emmm.201911466A paracrine activin A–mDia2 axis promotes squamous carcinogenesis via fibroblast reprogrammingMichael Cangkrama0Mateusz Wietecha1Nicolas Mathis2Rin Okumura3Luca Ferrarese4Dunja Al‐Nuaimi5Maria Antsiferova6Reinhard Dummer7Metello Innocenti8Sabine Werner9Department of Biology, Institute of Molecular Health Sciences, ETH ZurichDepartment of Biology, Institute of Molecular Health Sciences, ETH ZurichDepartment of Biology, Institute of Molecular Health Sciences, ETH ZurichDepartment of Biology, Institute of Molecular Health Sciences, ETH ZurichDepartment of Biology, Institute of Molecular Health Sciences, ETH ZurichDepartment of Biology, Institute of Molecular Health Sciences, ETH ZurichDepartment of Biology, Institute of Molecular Health Sciences, ETH ZurichDepartment of Dermatology, University Hospital ZurichHeidelberg University Biochemistry Center (BZH), Heidelberg UniversityDepartment of Biology, Institute of Molecular Health Sciences, ETH ZurichAbstract Cancer‐associated fibroblasts (CAFs) are key regulators of tumorigenesis and promising targets for next‐generation therapies. We discovered that cancer cell‐derived activin A reprograms fibroblasts into pro‐tumorigenic CAFs. Mechanistically, this occurs via Smad2‐mediated transcriptional regulation of the formin mDia2, which directly promotes filopodia formation and cell migration. mDia2 also induces expression of CAF marker genes through prevention of p53 nuclear accumulation, resulting in the production of a pro‐tumorigenic matrisome and secretome. The translational relevance of this finding is reflected by activin A overexpression in tumor cells and of mDia2 in the stroma of skin cancer and other malignancies and the correlation of high activin A/mDia2 levels with poor patient survival. Blockade of this signaling axis using inhibitors of activin, activin receptors, or mDia2 suppressed cancer cell malignancy and squamous carcinogenesis in 3D organotypic cultures, ex vivo, and in vivo, providing a rationale for pharmacological inhibition of activin A‐mDia2 signaling in stratified cancer patients.https://doi.org/10.15252/emmm.201911466activinCAFcarcinogenesismDia2tumor microenvironment |
| spellingShingle | Michael Cangkrama Mateusz Wietecha Nicolas Mathis Rin Okumura Luca Ferrarese Dunja Al‐Nuaimi Maria Antsiferova Reinhard Dummer Metello Innocenti Sabine Werner A paracrine activin A–mDia2 axis promotes squamous carcinogenesis via fibroblast reprogramming EMBO Molecular Medicine activin CAF carcinogenesis mDia2 tumor microenvironment |
| title | A paracrine activin A–mDia2 axis promotes squamous carcinogenesis via fibroblast reprogramming |
| title_full | A paracrine activin A–mDia2 axis promotes squamous carcinogenesis via fibroblast reprogramming |
| title_fullStr | A paracrine activin A–mDia2 axis promotes squamous carcinogenesis via fibroblast reprogramming |
| title_full_unstemmed | A paracrine activin A–mDia2 axis promotes squamous carcinogenesis via fibroblast reprogramming |
| title_short | A paracrine activin A–mDia2 axis promotes squamous carcinogenesis via fibroblast reprogramming |
| title_sort | paracrine activin a mdia2 axis promotes squamous carcinogenesis via fibroblast reprogramming |
| topic | activin CAF carcinogenesis mDia2 tumor microenvironment |
| url | https://doi.org/10.15252/emmm.201911466 |
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