A paracrine activin A–mDia2 axis promotes squamous carcinogenesis via fibroblast reprogramming

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...

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Bibliographic Details
Published in:EMBO molecular medicine Vol. 12; no. 4; pp. e11466 - n/a
Main Authors: Cangkrama, Michael, Wietecha, Mateusz, Mathis, Nicolas, Okumura, Rin, Ferrarese, Luca, Al‐Nuaimi, Dunja, Antsiferova, Maria, Dummer, Reinhard, Innocenti, Metello, Werner, Sabine
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 07.04.2020
EMBO Press
John Wiley and Sons Inc
Springer Nature
Subjects:
activin
Activin receptors
Activins - metabolism
Animals
CAF
Cancer therapies
Carcinogenesis
Carcinoma, Squamous Cell
Cell migration
EMBO03
EMBO38
Fibroblasts
Filopodia
Formins
Gene regulation
Genotype & phenotype
Humans
Malignancy
mDia2
Mice
Mice, Inbred NOD
Mice, SCID
Microtubule-Associated Proteins - metabolism
NADPH Dehydrogenase - metabolism
p53 Protein
Paracrine signalling
Secretome
Skin cancer
Smad2 protein
Stroma
Transcription
Tumor cells
tumor microenvironment
Tumorigenesis
Tumors
CAF
mDia2
tumor microenvironment
activin
carcinogenesis
ISSN:1757-4676, 1757-4684, 1757-4684
Online Access:Get full text
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Summary: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. Synopsis The growth and differentiation factor A induces differentiation of fibroblasts into tumor‐promoting cancer‐associated fibroblasts, thereby promoting cutaneous squamous carcinogenesis. Activin A promoted malignancy of squamous cell carcinoma in a non‐cell autonomous manner. Activin A induced a pro‐migratory and tumor‐promoting phenotype in fibroblasts via its direct target mDia2. mDia2 suppressed p53 activity in fibroblasts via direct protein‐protein interaction. Inhibition of the activin A‐mDia2 axis suppressed skin tumor growth. Graphical Abstract The growth and differentiation factor A induces differentiation of fibroblasts into tumor‐promoting cancer‐associated fibroblasts, thereby promoting cutaneous squamous carcinogenesis.
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See also: https://doi.org/10.15252/emmm.202012102 (April 2020)
ISSN:1757-4676
1757-4684
1757-4684
DOI:10.15252/emmm.201911466