The mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis
Open accessAbstract
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-β 1 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.
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mTOR, and more specifically the mTORC1/4E-BP1 signalling axis, plays a pivotal role in mediating the fibrogenic response to TGFβ1 stimulation in fibroblasts originating from multiple organs.
“We have shown that mTOR, and more specifically the mTORC1/4E-BP1 signalling axis, plays a pivotal role in mediating the fibrogenic response to TGFβ1 stimulation in fibroblasts originating from multiple organs, including the stromal reaction in cancer (Woodcock et al., 2019).”
From Pulmonary fibrosis: Emerging diagnostic and therapeutic strategies (2023) · cites this paper as Woodcock et al., 2019
IPF PCLSs have been used to evaluate the therapeutic effect, pharmacology, and mechanism of action of potential antifibrotic agents, including GSK2126458 (omipalisib), CZ415, GSK3008348, and EGCG.
“IPF PCLSs have been used to evaluate the therapeutic effect, pharmacology, and mechanism of action of potential antifibrotic agents, including the PI3K/AKT/mTOR inhibitor, GSK2126458 (omipalisib) (Mercer et al., 2016), the dual ATP-competitive mTOR inhibitor CZ415 (Woodcock et al., 2019), the αvβ6 inhibitor GSK3008348 (John et al., 2020), and the antifibrotic agent epigallocatechin gallate (EGCG”
From Pulmonary fibrosis: Emerging diagnostic and therapeutic strategies (2023) · cites this paper as Woodcock et al., 2019
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- Authors
- Woodcock, H. V., Eley, J. D., Guillotin, D., Platé, M., Nanthakumar, C. B., Martufi, M., Peace, S., Joberty, G., Poeckel, D., Good, R. B., Taylor, A. R., Zinn, N., Redding, M., Forty, E. J., Hynds, R. E., Swanton, C., Karsdal, M., Maher, T. M., Fisher, A., Bergamini, G., Marshall, R. P., Blanchard, A. D., Mercer, P. F., & Chambers, R. C.
- Affiliations
- University College London (GB)
- GlaxoSmithKline (United Kingdom) (GB)
- GlaxoSmithKline (Germany) (DE)
- The Francis Crick Institute (GB)
- Nordic Bioscience (Denmark) (DK)
- Imperial College London (GB)
- Newcastle University (GB)
- Corresponding author
- Chambers, Rachel C.
- ORCID
- Venue
- Nature Communications
- Published
- 2019-01-02
- Volume
- 10
- Issue
- 1
- Pages
- 6-6
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6315032
- OpenAlex
- W2907407196
- Cited by
- 224
- References
- 50
- Citations by year
- 2026: 20 · 2025: 20 · 2024: 26 · 2023: 27 · 2022: 40 · 2021: 41 · 2020: 37 · 2019: 12 · 2018: 1
- FWCI
- 17.14
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-09-11)
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- The Francis Crick Institute (cc-by)
- Funders
- GlaxoSmithKline
- Wellcome Trust (209199, C11496/A17786, FC001169, 209199/Z/17/Z, Z/17/Z)
- Francis Crick Institute (10169, FC001169)
- Cancer Research UK (C11496 / A17786, A17786, FC001169)
- National Institute for Health and Care Research
- University College London
- Newcastle University
- CRUK Lung Cancer Centre of Excellence
- Medical Research Council (MR/K024078/1, FC001169)
- Biotechnology and Biological Sciences Research Council (1488900, 1353894)
- NIHR Newcastle Biomedical Research Centre
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- mTORC1, 4E-BP1, fibrogenesis, idiopathic pulmonary fibrosis, myofibroblasts, TGF-β1, collagen synthesis, lung fibroblasts, PI3K/Akt signaling, mTOR inhibition, extracellular matrix deposition, matrisome, hepatic stellate cells, precision-cut lung slices, antifibrotic therapy
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Cell Line, Collagen, Fibroblasts, Humans, Phosphoproteins, Signal Transduction, Cell Cycle Proteins, Phosphatidylinositol 3-Kinases, Sirolimus, Adaptor Proteins, Signal Transducing, Transforming Growth Factor beta1, Idiopathic Pulmonary Fibrosis, TOR Serine-Threonine Kinases
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