s41467-018-07858-8.pdf (3.73 MB)
The mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis
journal contributionposted on 2019-12-19, 18:05 authored by Hannah V Woodcock, Jessica D Eley, Delphine Guillotin, Manuela Platé, Carmel B Nanthakumar, Matteo Martufi, Simon Peace, Gerard Joberty, Daniel Poeckel, Robert B Good, Adam R Taylor, Nico Zinn, Matthew Redding, Ellen J Forty, Robert E Hynds, Charles Swanton, Morten Karsdal, Toby M Maher, Giovanna Bergamini, Richard P Marshall, Andy D Blanchard, Paul F Mercer, Rachel C Chambers
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.
Crick (Grant ID: 10169, Grant title: Swanton FC001169)