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.

Cangkrama, M., Wietecha, M., Mathis, N., Okumura, R., Ferrarese, L., Al-Nuaimi, D., et al. (2020). A paracrine activin A–mDia2 axis promotes squamous carcinogenesis via fibroblast reprogramming. EMBO MOLECULAR MEDICINE, 12(4) [10.15252/emmm.201911466].

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

Innocenti, M;
2020

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.
Articolo in rivista - Articolo scientifico
activin; CAF; carcinogenesis; mDia2; tumor microenvironment;
English
2020
12
4
e11466
open
Cangkrama, M., Wietecha, M., Mathis, N., Okumura, R., Ferrarese, L., Al-Nuaimi, D., et al. (2020). A paracrine activin A–mDia2 axis promotes squamous carcinogenesis via fibroblast reprogramming. EMBO MOLECULAR MEDICINE, 12(4) [10.15252/emmm.201911466].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/396455
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