Cover Image

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...

Full description

Saved in:
Bibliographic Details
Main Authors: Cangkrama, Michael (Author) , Wietecha, Mateusz (Author) , Mathis, Nicolas (Author) , Okumura, Rin (Author) , Ferrarese, Luca (Author) , Al-Nuaimi, Dunja (Author) , Antsiferova, Maria (Author) , Dummer, Reinhard (Author) , Innocenti, Metello (Author) , Werner, Sabine (Author)
Format: Article (Journal)
Language:English
Published: 9 March 2020
In: EMBO molecular medicine
Year: 2020, Volume: 12, Issue: 4
ISSN:1757-4684
DOI:10.15252/emmm.201911466
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.15252/emmm.201911466
Verlag, lizenzpflichtig, Volltext: https://www.embopress.org/doi/full/10.15252/emmm.201911466
Get full text
Author Notes:Michael Cangkrama, Mateusz Wietecha, Nicolas Mathis, Rin Okumura, Luca Ferrarese, Dunja Al-Nuaimi, Maria Antsiferova, Reinhard Dummer, Metello Innocenti, Sabine Werner
Description
Summary: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.
Item Description:Gesehen am 07.01.2021
Physical Description:Online Resource
ISSN:1757-4684
DOI:10.15252/emmm.201911466

Similar Items