Alan Carruthers

Molecular Discovery (United Kingdom)

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Zoë Johnson

Roivant Sciences (Switzerland)

Ragini Medhi

Molecular Discovery (United Kingdom)

Lars van der Veen

Boehringer Ingelheim (Germany)

Marcel A. Deken

The Netherlands Cancer Institute

Hilary Sandig

Cancer Research UK Cambridge Center

Lauren Z. Maggs

Babraham Institute

Amy Fraser

Horizon Discovery Group (United Kingdom)

Simon A. Rudge

Cell Guidance Systems (United Kingdom)

Lynne A. Murray

AstraZeneca (United Kingdom)

Ashley B. Price

Detroit Public Library

Cooperative Institutions

AstraZeneca (United Kingdom)

AstraZeneca (United States)

University of Cambridge

Imperial College London

Inserm

Newcastle University

Aimmune Therapeutics (United Kingdom)

Babraham Institute

GlaxoSmithKline (United Kingdom)

AstraZeneca (Brazil)

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Autoantibodies are associated with disease progression in idiopathic pulmonary fibrosis

European Respiratory Journal (2023)

Katerina Koether Valérie Besnard Hilary Sandig Alan Carruthers Elena Miranda

Several reports have highlighted a potential role of autoreactive B-cells and autoantibodies that correlates with increased disease severity in patients with idiopathic pulmonary fibrosis (IPF). Here we show that patients with IPF have an altered B-cell phenotype and that those subjects who have autoantibodies against the intermediate filament protein periplakin (PPL) have a significantly worse outcome in terms of progression-free survival. Using a mouse model of lung fibrosis, we demonstrate that introducing antibodies targeting the endogenous protein PPL (mimicking naturally occurring autoantibodies seen in patients) directly in the lung increases lung injury, inflammation, collagen and fibronectin expression through direct activation of follicular dendritic cells, which in turn activates and drives proliferation of fibroblasts. This fibrocyte population was also observed in fibrotic foci of patients with IPF and was increased in peripheral blood of IPF patients compared to aged-matched controls. This study reiterates the complex and heterogeneous nature of IPF, identifying new pathways that may prove suitable for therapeutic intervention.

Fibrocyte

10.1183/13993003.02381-2021

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Citations (12)

Pancreatic CAF-derived Autotaxin (ATX) drives autocrine CTGF expression to modulate pro-tumorigenic signaling

Molecular Cancer Therapeutics (2024)

Fanny Volat Ragini Medhi Lauren Z. Maggs Marcel A. Deken Ashley B. Price

Abstract Autotaxin (ATX), encoded by ENPP2, is a clinical target in pancreatic ductal adenocarcinoma (PDAC). ATX catalyzes the production of lysophosphatidic acid (LPA), an important regulator within the tumor microenvironment (TME), yet the pro-tumorigenic action of the ATX/LPA axis in PDAC remains unclear. Here, by interrogating patient samples and cell line datasets, we show that the PDAC TME, rather than cancer cells, is responsible for the majority of ENPP2 expression, and highlight a key role for cancer associated fibroblast (CAF)-derived ATX in autocrine and paracrine pro-tumorigenic signaling. Using the clinical-stage ATX inhibitor, IOA-289, we identified connective tissue growth factor (CTGF) as a downstream mediator of ATX signaling in the PDAC CAF-derived cell line, 0082T. Genetic ablation or pharmacological inhibition of ATX in 0082T CAFs reduced CTGF secretion via modulation of LPA/LPA receptor (LPAR) signaling. Despite the loss of ATX function, extracellular levels of LPA were paradoxically increased, indicating a role for ATX beyond its enzymatic activity and suggesting a role for its LPA chaperone function in the LPA/LPAR signaling in CAFs. As CAFs are the main source for CTGF in the PDAC TME, these findings suggest a role for ATX in promoting pro-tumorigenic microenvironment via modulation of CAF secretion, not only via its LPA-producing activity but also via its LPA chaperone function, providing a potential mechanism for the anti-tumor effects of ATX inhibition.

Autotaxin

10.1158/1535-7163.mct-23-0522

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Divergent roles for Clusterin in Lung Injury and Repair

Scientific Reports (2017)

David M. Habiel Ana Camelo Milena S. Espíndola Timothy Burwell Richard N. Hanna

Lung fibrosis is an unabated wound healing response characterized by the loss and aberrant function of lung epithelial cells. Herein, we report that extracellular Clusterin promoted epithelial cell apoptosis whereas intracellular Clusterin maintained epithelium viability during lung repair. Unlike normal and COPD lungs, IPF lungs were characterized by significantly increased extracellular Clusterin whereas the inverse was evident for intracellular Clusterin. In vitro and in vivo studies demonstrated that extracellular Clusterin promoted epithelial cell apoptosis while intercellular Clusterin modulated the expression of the DNA repair proteins, MSH2, MSH6, OGG1 and BRCA1. The fibrotic response in Clusterin deficient (CLU-/-) mice persisted after bleomycin and it was associated with increased DNA damage, reduced DNA repair responses, and elevated cellular senescence. Remarkably, this pattern mirrored that observed in IPF lung tissues. Together, our results show that cellular localization of Clusterin leads to divergent effects on epithelial cell regeneration and lung repair during fibrosis.

Clusterin

10.1038/s41598-017-15670-5

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Citations (33)

FPR-1 is an important regulator of neutrophil recruitment and a tissue-specific driver of pulmonary fibrosis

JCI Insight (2020)

Jack Leslie Ben Millar Alicia del Carpio Pons Rachel A. Burgoyne Joseph D. Frost

Neutrophils are the most abundant inflammatory cells at the earliest stages of wound healing and play important roles in wound repair and fibrosis. Formyl peptide receptor 1 (FPR-1) is abundantly expressed on neutrophils and has been shown to regulate their function, yet the importance of FPR-1 in fibrosis remains ill defined. FPR-1–deficient (fpr1–/–) mice were protected from bleomycin-induced pulmonary fibrosis but developed renal and hepatic fibrosis normally. Mechanistically, we observed a failure to effectively recruit neutrophils to the lungs of fpr1–/– mice, whereas neutrophil recruitment was unaffected in the liver and kidney. Using an adoptive transfer model we demonstrated that the defect in neutrophil recruitment to the lung was intrinsic to the fpr1–/– neutrophils, as C57BL/6 neutrophils were recruited normally to the damaged lung in fpr1–/– mice. Finally, C57BL/6 mice in which neutrophils had been depleted were protected from pulmonary fibrosis. In conclusion, FPR-1 and FPR-1 ligands are required for effective neutrophil recruitment to the damaged lung. Failure to recruit neutrophils or depletion of neutrophils protects from pulmonary fibrosis.

10.1172/jci.insight.125937

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Citations (70)

Supplementary Figure S6 from Pancreatic CAF-Derived Autotaxin Drives Autocrine CTGF Expression to Modulate Protumorigenic Signaling

Fanny Volat Ragini Medhi Lauren Z. Maggs Marcel A. Deken Ashley B. Price

<p>Supplementary Figure S6 shows LLPs expression in PDAC cancer and CAFs cells.</p>

Autotaxin

Expression (computer science)

10.1158/1535-7163.28342339

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Sensitization of the UPR by Loss of PPP1R15A Promotes Fibrosis and Senescence in IPF

Research Square (Research Square) (2021)

Susan J. Monkley Catherine Overed-Sayer Helen Parfrey Doris M. Rassl Damian C. Crowther

Abstract The unfolded protein response (UPR) is a direct consequence of cellular endoplasmic reticulum (ER) stress and a key disease driving mechanism in IPF. The resolution of the UPR is directed by PPP1R15A (GADD34) and leads to the restoration of normal ribosomal activity. While the role of PPP1R15A has been explored in lung epithelial cells, the role of this UPR resolving factor has yet to be explored in lung mesenchymal cells. The objective of the current study was to determine the expression and role of PPP1R15A in IPF fibroblasts and in a bleomycin-induced lung fibrosis model. A survey of IPF lung tissue revealed that PPP1R15A expression was markedly reduced. Targeting PPP1R15A in primary fibroblasts modulated TGF-b-induced fibroblast to myofibroblast differentiation and exacerbated pulmonary fibrosis in bleomycin-challenged mice. Interestingly, the loss of PPP1R15A appeared to promote lung fibroblast senescence. Taken together, our findings demonstrate the major role of PPP1R15A in the regulation of lung mesenchymal cells, and regulation of PPP1R15A may represent a novel therapeutic strategy in IPF.

Myofibroblast

Senescence

10.21203/rs.3.rs-480385/v1

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An Anti-Human ICAM-1 Antibody Inhibits Rhinovirus-Induced Exacerbations of Lung Inflammation

PLoS Pathogens (2013)

Stephanie Traub Alexandra Nikonova Alan Carruthers Rebecca Dunmore Katherine A. Vousden

Human rhinoviruses (HRV) cause the majority of common colds and acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Effective therapies are urgently needed, but no licensed treatments or vaccines currently exist. Of the 100 identified serotypes, ∼90% bind domain 1 of human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor, making this an attractive target for development of therapies; however, ICAM-1 domain 1 is also required for host defence and regulation of cell trafficking, principally via its major ligand LFA-1. Using a mouse anti-human ICAM-1 antibody (14C11) that specifically binds domain 1 of human ICAM-1, we show that 14C11 administered topically or systemically prevented entry of two major groups of rhinoviruses, HRV16 and HRV14, and reduced cellular inflammation, pro-inflammatory cytokine induction and virus load in vivo. 14C11 also reduced cellular inflammation and Th2 cytokine/chemokine production in a model of major group HRV-induced asthma exacerbation. Interestingly, 14C11 did not prevent cell adhesion via human ICAM-1/LFA-1 interactions in vitro, suggesting the epitope targeted by 14C11 was specific for viral entry. Thus a human ICAM-1 domain-1-specific antibody can prevent major group HRV entry and induction of airway inflammation in vivo.

Rhinovirus

10.1371/journal.ppat.1003520

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Citations (71)

The application of sequence stratigraphy to the understanding of Late Jurassic turbidite plays in the Central North Sea, UKCS

Geological Society London Special Publications (1996)

Alan Carruthers Tom McKie John D. Price Robin Dyer G. Williams

Abstract The identification and correlation of genetic sequences has significantly enhanced our understanding of the Late Jurassic stratigraphy in the Central North Sea. The integration of genetic sequences with an appreciation of the basinal mudrock stratigraphy, and the identification of depositional sequence boundaries provides a powerful tool to understand and potentially predict the distribution of subtle stratigraphic turbidite plays. The largely syn-rift Late Oxfordian-Kimmeridgian was deposited during a low frequency, second-order sea-level rise, culminating in the eudoxus condensed section. Deposition was dominated by shallow marine shelfal sandstones and offshore mudrocks. Sandy turbidites are rare. Whilst the requisite depositional slopes and deep water areas are likely to have existed, the effects of high frequency relative sea-level falls are likely to have been suppressed. As the second-order sea-level rise accelerated towards the eudoxus condensed section, the supply of sand into the basin was reduced such that the potential for turbidite deposits was minimal. The largely post-rift Kimmeridgian-Volgian section is dominated by basinal mudrocks. However, regionally correlatable ‘hot’ and ‘cool’ units provide information on sediment flux into the basin which may be linked to relative sea-level changes on the basin margin, with cool units interpreted to be the product of enhanced depositional rates during lowstand. Turbidites commonly occur within the ‘cool’ mudrock units. A Middle Volgian ‘cool’ unit is likely to represent a second-order sea-level fall, within which are composite turbidite packages which are considered to be the product of higher frequency lowstands (lowstand sequence set).

Sequence (biology)

Sequence Stratigraphy

10.1144/gsl.sp.1996.114.01.02

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Citations (22)

Sensitization of the UPR by loss of PPP1R15A promotes fibrosis and senescence in IPF

Scientific Reports (2021)

Susan J. Monkley Catherine Overed-Sayer Helen Parfrey Doris M. Rassl Damian C. Crowther

The unfolded protein response (UPR) is a direct consequence of cellular endoplasmic reticulum (ER) stress and a key disease driving mechanism in IPF. The resolution of the UPR is directed by PPP1R15A (GADD34) and leads to the restoration of normal ribosomal activity. While the role of PPP1R15A has been explored in lung epithelial cells, the role of this UPR resolving factor has yet to be explored in lung mesenchymal cells. The objective of the current study was to determine the expression and role of PPP1R15A in IPF fibroblasts and in a bleomycin-induced lung fibrosis model. A survey of IPF lung tissue revealed that PPP1R15A expression was markedly reduced. Targeting PPP1R15A in primary fibroblasts modulated TGF-β-induced fibroblast to myofibroblast differentiation and exacerbated pulmonary fibrosis in bleomycin-challenged mice. Interestingly, the loss of PPP1R15A appeared to promote lung fibroblast senescence. Taken together, our findings demonstrate the major role of PPP1R15A in the regulation of lung mesenchymal cells, and regulation of PPP1R15A may represent a novel therapeutic strategy in IPF.

Senescence

Myofibroblast

10.1038/s41598-021-00769-7

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Citations (15)

Supplementary Figure S1 from Pancreatic CAF-Derived Autotaxin Drives Autocrine CTGF Expression to Modulate Protumorigenic Signaling

Fanny Volat Ragini Medhi Lauren Z. Maggs Marcel A. Deken Ashley B. Price

<p>Supplementary Figure S1 shows the validation of ESTIMATE stromal and immune gene signatures and mRNA expression in tumour-rich and TME-rich samples.</p>

Autotaxin

CYR61

Expression (computer science)

10.1158/1535-7163.28342357

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Citations (0)