The MTORC1/4E-BP1 Axis Represents a Critical Signaling Node During Fibrogenesis

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Jan 4

PMID 30602778

Citations 101

Authors

Hannah V Woodcock

Jessica D Eley

Delphine Guillotin

Manuela Plate

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

Andrew Fisher

Giovanna Bergamini

Richard P Marshall

Andy D Blanchard

Paul F Mercer

Rachel C Chambers

Affiliations

Soon will be listed here.

Abstract

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 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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References

Akhurst R . Targeting TGF-β Signaling for Therapeutic Gain. Cold Spring Harb Perspect Biol. 2017; 9(10). PMC: 5630004. DOI: 10.1101/cshperspect.a022301. View

Verrecchia F, Chu M, Mauviel A . Identification of novel TGF-beta /Smad gene targets in dermal fibroblasts using a combined cDNA microarray/promoter transactivation approach. J Biol Chem. 2001; 276(20):17058-62. DOI: 10.1074/jbc.M100754200. View

Horowitz J, Rogers D, Sharma V, Vittal R, White E, Cui Z . Combinatorial activation of FAK and AKT by transforming growth factor-beta1 confers an anoikis-resistant phenotype to myofibroblasts. Cell Signal. 2006; 19(4):761-71. PMC: 1820832. DOI: 10.1016/j.cellsig.2006.10.001. View

Alvarez D, Cardenes N, Sellares J, Bueno M, Corey C, Hanumanthu V . IPF lung fibroblasts have a senescent phenotype. Am J Physiol Lung Cell Mol Physiol. 2017; 313(6):L1164-L1173. PMC: 6148001. DOI: 10.1152/ajplung.00220.2017. View

Bremnes R, Donnem T, Al-Saad S, Al-Shibli K, Andersen S, Sirera R . The role of tumor stroma in cancer progression and prognosis: emphasis on carcinoma-associated fibroblasts and non-small cell lung cancer. J Thorac Oncol. 2010; 6(1):209-17. DOI: 10.1097/JTO.0b013e3181f8a1bd. View

Malouf M, Hopkins P, Snell G, Glanville A . An investigator-driven study of everolimus in surgical lung biopsy confirmed idiopathic pulmonary fibrosis. Respirology. 2011; 16(5):776-83. DOI: 10.1111/j.1440-1843.2011.01955.x. View

Mora A, Rojas M, Pardo A, Selman M . Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease. Nat Rev Drug Discov. 2017; 16(11):755-772. DOI: 10.1038/nrd.2017.170. View

Yang I, Schwartz D . Epigenetics of idiopathic pulmonary fibrosis. Transl Res. 2014; 165(1):48-60. PMC: 4182166. DOI: 10.1016/j.trsl.2014.03.011. View

Huang J, Manning B . The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J. 2008; 412(2):179-90. PMC: 2735030. DOI: 10.1042/BJ20080281. View

10.

Leeming D, Larsen D, Zhang C, Hi Y, Veidal S, Nielsen R . Enzyme-linked immunosorbent serum assays (ELISAs) for rat and human N-terminal pro-peptide of collagen type I (PINP)--assessment of corresponding epitopes. Clin Biochem. 2010; 43(15):1249-56. DOI: 10.1016/j.clinbiochem.2010.07.025. View

11.

Mendoza M, Er E, Blenis J . The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci. 2011; 36(6):320-8. PMC: 3112285. DOI: 10.1016/j.tibs.2011.03.006. View

12.

Vizcaino J, Csordas A, Del-Toro N, Dianes J, Griss J, Lavidas I . 2016 update of the PRIDE database and its related tools. Nucleic Acids Res. 2015; 44(D1):D447-56. PMC: 4702828. DOI: 10.1093/nar/gkv1145. View

13.

Thoreen C, Chantranupong L, Keys H, Wang T, Gray N, Sabatini D . A unifying model for mTORC1-mediated regulation of mRNA translation. Nature. 2012; 485(7396):109-13. PMC: 3347774. DOI: 10.1038/nature11083. View

14.

Mercer P, Woodcock H, Eley J, Plate M, Sulikowski M, Durrenberger P . Exploration of a potent PI3 kinase/mTOR inhibitor as a novel anti-fibrotic agent in IPF. Thorax. 2016; 71(8):701-11. PMC: 4975851. DOI: 10.1136/thoraxjnl-2015-207429. View

15.

Laplante M, Sabatini D . mTOR signaling in growth control and disease. Cell. 2012; 149(2):274-93. PMC: 3331679. DOI: 10.1016/j.cell.2012.03.017. View

16.

Heudel P, Fabbro M, Roemer-Becuwe C, Kaminsky M, Arnaud A, Joly F . Phase II study of the PI3K inhibitor BKM120 in patients with advanced or recurrent endometrial carcinoma: a stratified type I-type II study from the GINECO group. Br J Cancer. 2017; 116(3):303-309. PMC: 5294485. DOI: 10.1038/bjc.2016.430. View

17.

King Jr T, Bradford W, Castro-Bernardini S, Fagan E, Glaspole I, Glassberg M . A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014; 370(22):2083-92. DOI: 10.1056/NEJMoa1402582. View

18.

Hinz B . The role of myofibroblasts in wound healing. Curr Res Transl Med. 2016; 64(4):171-177. DOI: 10.1016/j.retram.2016.09.003. View

19.

White E, Atrasz R, Hu B, Phan S, Stambolic V, Mak T . Negative regulation of myofibroblast differentiation by PTEN (Phosphatase and Tensin Homolog Deleted on chromosome 10). Am J Respir Crit Care Med. 2005; 173(1):112-21. PMC: 1434700. DOI: 10.1164/rccm.200507-1058OC. View

20.

Chen C, Peng Y, Wang Z, Fish P, Kaar J, Koepsel R . The Scar-in-a-Jar: studying potential antifibrotic compounds from the epigenetic to extracellular level in a single well. Br J Pharmacol. 2009; 158(5):1196-209. PMC: 2782330. DOI: 10.1111/j.1476-5381.2009.00387.x. View