A paracrine activin A-mDia2 axis promotes squamous carcinogenesis via fibroblast reprogramming.
CAF
activin
carcinogenesis
mDia2
tumor microenvironment
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
07 04 2020
07 04 2020
Historique:
received:
20
09
2019
revised:
06
02
2020
accepted:
10
02
2020
pubmed:
10
3
2020
medline:
29
7
2021
entrez:
10
3
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32150356
doi: 10.15252/emmm.201911466
pmc: PMC7136968
doi:
Substances chimiques
Formins
0
Microtubule-Associated Proteins
0
activin A
0
Activins
104625-48-1
Dia2 protein, mouse
EC 1.6.99.1
NADPH Dehydrogenase
EC 1.6.99.1
Banques de données
GEO
['GSE130017']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e11466Subventions
Organisme : Cancer Research Switzerland
ID : KFS-4510-08-2018
Pays : International
Organisme : University Medicine Zurich (Project SKINTEGRITY)
Pays : International
Organisme : Swiss National Science Foundation
ID : 31003A_169204
Pays : Switzerland
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2020 The Authors. Published under the terms of the CC BY 4.0 license.
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