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CXCL14 Is a Candidate Biomarker for Hedgehog Signalling in Idiopathic

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CXCL14 Is a Candidate Biomarker for Hedgehog Signalling in Idiopathic Thorax Online First, published on March 1, 2017 as 10.1136/thoraxjnl-2015-207682 Biomarkers of disease ORIGINAL ARTICLE Thorax: first published as 10.1136/thoraxjnl-2015-207682 on 1 March 2017. Downloaded from CXCL14 is a candidate biomarker for Hedgehog signalling in idiopathic pulmonary fibrosis Guiquan Jia,1 Sanjay Chandriani,1 Alexander R Abbas,1 Daryle J DePianto,1 Elsa N N’Diaye,1 Murat B Yaylaoglu,1 Heather M Moore,1 Ivan Peng,1 Jason DeVoss,1 Harold R Collard,2 Paul J Wolters,2 Jackson G Egen,1 Joseph R Arron1 ▸ Additional material is ABSTRACT published online only. To view Background Idiopathic pulmonary fibrosis (IPF) is Key messages please visit the journal online (http://dx.doi.org/10.1136/ associated with aberrant expression of developmental thoraxjnl-2015-207682). pathways, including Hedgehog (Hh). As Hh signalling contributes to multiple pro-fibrotic processes, Hh 1Genentech, Inc., South What is the key question? San Francisco, California, USA inhibition may represent a therapeutic option for IPF. ▸ How can activity of the profibrotic Hedgehog 2Division of Pulmonary and However, no non-invasive biomarkers are available to signalling pathway be monitored non-invasively Critical Care Medicine, monitor lung Hh activity. in patients with idiopathic pulmonary fibrosis Department of Medicine, Methods We assessed gene and protein expression in (IPF)? University of California, fi San Francisco, California, USA IPF and control lung biopsies, mouse lung, broblasts stimulated in vitro with sonic hedgehog (SHh), and What is the bottom line? ▸ Correspondence to plasma in IPF patients versus controls, and cancer Using human IPF lung tissue and blood, in vitro Dr Joseph R Arron, Genentech, patients before and after treatment with vismodegib, cell culture, in vivo animal models and blood Inc., MS 34, 1 DNA Way, a Hh inhibitor. samples from an interventional clinical study, South San Francisco, CA we show that CXCL14 is a candidate blood 94080, USA; arron.joseph@ Results Lung tissue from IPF patients exhibited gene.com significantly greater expression of Hh-related genes biomarker of Hedgehog pathway activity in IPF. fi versus controls. The gene most signi cantly upregulated Why read on? Received 9 August 2015 in both IPF lung biopsies and fibroblasts stimulated in Revised 31 January 2017 ▸ The ability to monitor the activity of key Accepted 3 February 2017 vitro with SHh was CXCL14, which encodes a soluble signalling pathways non-invasively may aid in secreted chemokine whose expression is inhibited in vitro the development of molecularly targeted by the addition of vismodegib. CXCL14 expression therapies for IPF. was induced by SHh overexpression in mouse lung. Circulating CXCL14 protein levels were significantly http://thorax.bmj.com/ higher in plasma from IPF patients than controls. In cancer patients, circulating CXCL14 levels were development and patterning such as Wnt and significantly reduced upon vismodegib treatment. Hedgehog (Hh) are reactivated in IPF and may con- 4–10 Conclusions CXCL14 is a systemic biomarker that tribute to fibrogenesis. Sonic Hedgehog (SHh) could be used to identify IPF patients with increased is essential for branching morphogenesis in the 11 Hh pathway activity and monitor the pharmacodynamic developing lung; overexpression of SHh in effects of Hh antagonist therapy in IPF. mouse embryos results in the accumulation of 12 on September 26, 2021 by guest. Protected copyright. Trial registration number Post-results, NCT00968981. excessive mesenchymal tissue. In healthy adult tissue, there is minimal evidence for Hh activity. Bleomycin-mediated lung injury induces Hh pathway activity and SHh overexpression increases INTRODUCTION fibrotic collagen deposition in the context of bleo- Idiopathic pulmonary fibrosis (IPF) is a chronic, mycin injury.13 Hh activity in human lung fibro- progressive and lethal fibrotic disease of unclear blasts can promote multiple profibrotic processes, aetiology leading to irreversible scarring of the lung including enhanced sensitivity to TGFβ and PDGF, parenchyma and loss of lung function.1 Genetic leading to increased migration, contractility and predisposition to pulmonary fibrosis implicates type survival,56while epithelial cell-derived SHh and 2 alveolar epithelial cell (AEC2) dysfunction in fibroblast-derived TGFβ can reciprocally induce disease pathogenesis and suggests that increased each other;14 these epithelial–mesenchymal interac- susceptibility of the alveolar epithelium to accumu- tions collectively can contribute to pathological lated environmental insults promotes an aberrant fibrosis. wound healing response in the underlying mesen- Canonical Hh signalling is a highly regulated chymal cells, resulting in myofibroblast differenti- process. In the constitutive unliganded ‘off’ state, ation, proliferation and excessive extracellular patched transmembrane receptors (eg, PTCH1 and To cite: Jia G, Chandriani S, matrix (ECM) deposition.2 PTCH2) inhibit the activity of smoothened (SMO), Abbas AR, et al. Thorax Published Online First: Multiple molecular pathways are aberrantly maintaining its localisation to intracellular endo- [please include Day Month expressed in IPF tissue including directly pro- somes. When a secreted Hh ligand, for example, Year] doi:10.1136/thoraxjnl- fibrotic mediators such as TGFβ, IL13 and FGF.3 SHh, binds to PTCH, SMO repression is released 2015-207682 In addition, pathways implicated in embryonic and SMO accumulates in the primary cilium, Jia G, et al. Thorax 2017;0:1–8. doi:10.1136/thoraxjnl-2015-207682 1 Copyright Article author (or their employer) 2017. Produced by BMJ Publishing Group Ltd (& BTS) under licence. Biomarkers of disease disrupting constitutive proteolysis of GLI transcription factors immunohistochemistry (IHC) for localisation of CXCL14 Thorax: first published as 10.1136/thoraxjnl-2015-207682 on 1 March 2017. Downloaded from and resulting in translocation of intact GLI to the nucleus where protein and non-isotopic RNA in situ hybridisation (ISH). it can activate transcription of target genes. Importantly, GLI itself is a transcriptional target of Hh pathway activity, resulting Statistical analyses in a positive feedback loop.10 15 Statistical analyses were performed in R. Relationships between Basal cell carcinoma (BCC) of the skin is the most common gene expression and plasma protein concentration across patient form of cancer and is characterised by excessive activity of the groups were tested by the Wilcoxon rank-sum method. Mouse Hh pathway. Individuals with Gorlin syndrome carry inactivat- lung gene expression was analysed by Student’s t-test with ing mutations in PTCH1, resulting in excessive Hh activity in Welch’s correction for unequal SDs. Plasma biomarker changes the skin and multiple aggressive, recurrent BCCs.16 Vismodegib, over time were analysed by Student’s paired t-test. Each time- a small molecule inhibitor of SMO, reduces the growth and point was compared to baseline, with adjustment for multiple invasiveness of locally advanced and metastatic BCC, and is an testing by the permutation method. A p value <0.05 was con- approved therapy for that indication.17 sidered statistically significant. p Value correction for testing of Targeting the Hh pathway may be a potential therapeutic multiple hypotheses in gene expression analyses was performed option for IPF. However, molecular, pathological and clinical by applying the Benjamini-Hochberg method as implemented in heterogeneity in IPF patients18 makes it difficult to monitor the R package limma. molecular responsiveness to treatment and identify those most likely to benefit from therapy without directly sampling lung RESULTS tissue, which poses risks to patients and is logistically impractical Gene expression patterns in IPF implicate Hh pathway in large multicentre clinical studies. Therefore, we sought to activity characterise Hh pathway activity in IPF lungs and identify candi- We have previously reported the assessment of gene expression date non-invasive biomarkers related to Hh activity that could in lung biopsies from patients with IPF (N=40) and control be used as pharmacodynamic and/or predictive indicators of unused donor lung tissue (N=8) using qPCR19 and genome- treatment effects. wide microarrays.21 In addition to evidence for activity of profi- brotic signalling pathways such as IL1319 and consistent with 56 METHODS other published reports, we observed transcriptional evidence Detailed methods can be found in the online supplement. for activity of the Hh signalling pathway. In the genome-wide analysis, Hh pathway transcription factors GLI1 (4.3-fold) and GLI2 Patient samples (threefold) and the transmembrane activating protein SMO fi All tissues, plasma samples and clinical data for IPF were (2.6-fold) were among the signi cantly differentially upre- fi obtained as described previously.19 gulated transcripts in IPF as compared to control. To con rm SHH4610g was a multicentre, two-stage, open-label phase Ib the expression of these transcripts and explore other Hh study designed to describe the pharmacokinetics (PK) of vismo- pathway genes, we performed qPCR on the same biopsy SHH degib (GDC-0449, a small molecule SMO inhibitor) in 63 samples. We observed slightly decreased expression of and PTCH1 fi http://thorax.bmj.com/ safety-evaluable patients with advanced solid tumours that were in IPF relative to control and signi cantly elevated GLI1 GLI2 SMO PTCH2 refractory to treatment or for whom no standard therapy expression of , , and in IPF relative to fi existed.20
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