SRC and TKS5 mediated podosome formation in fibroblasts promotes extracellular matrix invasion and pulmonary fibrosis

Ilianna Barbayianni, Paraskevi Kanellopoulou, Dionysios Fanidis, Dimitris Nastos, Eleftheria-Dimitra Ntouskou, Apostolos Galaris, Vaggelis Harokopos, Pantelis Hatzis, Eliza Tsitoura, Robert Homer, Naftali Kaminski, Katerina M. Antoniou, Bruno Crestani, Argyrios Tzouvelekis and Vassilis Aidinis ()
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Ilianna Barbayianni: Biomedical Sciences Research Center Alexander Fleming
Paraskevi Kanellopoulou: Biomedical Sciences Research Center Alexander Fleming
Dionysios Fanidis: Biomedical Sciences Research Center Alexander Fleming
Dimitris Nastos: Biomedical Sciences Research Center Alexander Fleming
Eleftheria-Dimitra Ntouskou: Biomedical Sciences Research Center Alexander Fleming
Apostolos Galaris: Biomedical Sciences Research Center Alexander Fleming
Vaggelis Harokopos: Biomedical Sciences Research Center Alexander Fleming
Pantelis Hatzis: Biomedical Sciences Research Center Alexander Fleming
Eliza Tsitoura: University of Crete
Robert Homer: Yale School of Medicine
Naftali Kaminski: Yale School of Medicine
Katerina M. Antoniou: University of Crete
Bruno Crestani: Bichat-Claude Bernard Hospital
Argyrios Tzouvelekis: University of Patras
Vassilis Aidinis: Biomedical Sciences Research Center Alexander Fleming

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract The activation and accumulation of lung fibroblasts resulting in aberrant deposition of extracellular matrix components, is a pathogenic hallmark of Idiopathic Pulmonary Fibrosis, a lethal and incurable disease. In this report, increased expression of TKS5, a scaffold protein essential for the formation of podosomes, was detected in the lung tissue of Idiopathic Pulmonary Fibrosis patients and bleomycin-treated mice. Τhe profibrotic milieu is found to induce TKS5 expression and the formation of prominent podosome rosettes in lung fibroblasts, that are retained ex vivo, culminating in increased extracellular matrix invasion. Tks5+/- mice are found resistant to bleomycin-induced pulmonary fibrosis, largely attributed to diminished podosome formation in fibroblasts and decreased extracellular matrix invasion. As computationally predicted, inhibition of src kinase is shown to potently attenuate podosome formation in lung fibroblasts and extracellular matrix invasion, and bleomycin-induced pulmonary fibrosis, suggesting pharmacological targeting of podosomes as a very promising therapeutic option in pulmonary fibrosis.

Date: 2023
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DOI: 10.1038/s41467-023-41614-x

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