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Lookup NU author(s): Professor Andrew FisherORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2019, The Author(s).Myofibroblasts are the key effector cells responsible for excessive extracellular matrix deposition in multiple fibrotic conditions, including idiopathic pulmonary fibrosis (IPF). The PI3K/Akt/mTOR axis has been implicated in fibrosis, with pan-PI3K/mTOR inhibition currently under clinical evaluation in IPF. Here we demonstrate that rapamycin-insensitive mTORC1 signaling via 4E-BP1 is a critical pathway for TGF-β1 stimulated collagen synthesis in human lung fibroblasts, whereas canonical PI3K/Akt signaling is not required. The importance of mTORC1 signaling was confirmed by CRISPR-Cas9 gene editing in normal and IPF fibroblasts, as well as in lung cancer-associated fibroblasts, dermal fibroblasts and hepatic stellate cells. The inhibitory effect of ATP-competitive mTOR inhibition extended to other matrisome proteins implicated in the development of fibrosis and human disease relevance was demonstrated in live precision-cut IPF lung slices. Our data demonstrate that the mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis with potential implications for the development of novel anti-fibrotic strategies.
Author(s): Woodcock HV, Eley JD, Guillotin D, Plate M, Nanthakumar CB, Martufi M, Peace S, Joberty G, Poeckel D, Good RB, Taylor AR, Zinn N, Redding M, Forty EJ, Hynds RE, Swanton C, Karsdal M, Maher TM, Fisher A, Bergamini G, Marshall RP, Blanchard AD, Mercer PF, Chambers RC
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2019
Volume: 10
Print publication date: 01/12/2019
Online publication date: 02/01/2019
Acceptance date: 29/11/2018
Date deposited: 16/12/2020
ISSN (electronic): 2041-1723
Publisher: Nature Publishing Group
URL: https://doi.org/10.1038/s41467-018-07858-8
DOI: 10.1038/s41467-018-07858-8
PubMed id: 30602778
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