Ann-Christin Cichon

University College London

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Andrew W. Stoker

University College London

Dennis J. McCance

Queen's University Belfast

Dagan Jenkins

University College London

Jeshmi Jeyabalan

University College London

Adam Pickard

St George’s University Hospitals NHS Foundation Trust

Víctor Hernández-Hernández

Brunel University of London

Peter Scambler

University College London

Maartje J. Geerlings

Radboud University Nijmegen

Peggy Lim

D. Patel

Energetics (United States)

Cooperative Institutions

University College London

Great Ormond Street Hospital

Queen's University Belfast

University of Oxford

Universidade de São Paulo

John Radcliffe Hospital

Instituto Biológico

University of Ulster

Cancer Research UK

King's College London

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AKT in Stromal Fibroblasts Controls Invasion of Epithelial Cells

Oncotarget (2013)

Ann-Christin Cichon Adam Pickard Simon S. McDade Daniel Sharpe Michael Moran

// Ann-Christin Cichon 1,* , Adam Pickard 1,* , Simon S. McDade 1 , Daniel J. Sharpe 1 , Michael Moran 1 , Jacqueline A. James 1 and Dennis J. McCance 1 1 Centre for Cancer Research and Cell Biology, Queen's University, Belfast, UK * These authors contributed equally Correspondence: Dennis J. McCance, email: // Keywords : stroma, invasion, AKT, Caspase 1, HPV, mdm2, interleukin 1, KGF, cancer Received : June 7, 2013 Accepted : July 11, 2013 Published : July 14, 2013 Abstract The tumour microenvironment has an important role in cancer progression and recent reports have proposed that stromal AKT is activated and regulates tumourigenesis and invasion. We have shown, by immuno-fluorescent analysis of oro-pharyngeal cancer biopsies, an increase in AKT activity in tumour associated stromal fibroblasts compared to normal stromal fibroblasts. Using organotypic raft co-cultures, we show that activation of stromal AKT can induce the invasion of keratinocytes expressing the HPV type 16 E6 and E7 proteins, in a Keratinocyte Growth Factor (KGF) dependent manner. By depleting stromal fibroblasts of each of the three AKT isoforms independently, or through using isoform specific inhibitors, we determined that stromal AKT2 is an essential regulator of invasion and show in oro-pharyngeal cancers that AKT2 specific phosphorylation events are also identified in stromal fibroblasts. Depletion of stromal AKT2 inhibits epithelial invasion through activating a protective pathway counteracting KGF mediated invasions. AKT2 depletion in fibroblasts stimulates the cleavage and release of IL1B from stromal fibroblasts resulting in down-regulation of the KGF receptor (fibroblast growth factor receptor 2B (FGFR2B)) expression in the epithelium. We also show that high IL1B is associated with increased overall survival in a cohort of patients with oro-pharyngeal cancers. Our findings demonstrate the importance of stromal derived growth factors and cytokines in regulating the process of tumour cell invasion.

AKT2

10.18632/oncotarget.1078

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Citations (19)

Supplementary Material for: An FDA-Approved Drug Screen for Compounds Influencing Craniofacial Skeletal Development and Craniosynostosis

Figshare (2018)

Marian Seda Mirjam I. Geerlings Poong Lim Jeshmi Jeyabalan Ann-Christin Cichon

Neural crest stem/progenitor cells (NCSCs) populate a variety of tissues, and their dysregulation is implicated in several human diseases including craniosynostosis and neuroblastoma. We hypothesised that small molecules that inhibit NCSC induction or differentiation may represent potential therapeutically relevant drugs in these disorders. We screened 640 FDA-approved compounds currently in clinical use for other conditions to identify those which disrupt development of NCSC-derived skeletal elements that form the zebrafish jaw. In the primary screen, we used heterozygous transgenic sox10:gfp zebrafish to directly visualise NCSC-derived jaw cartilage. We noted partial toxicity of this transgene in relation to jaw patterning, suggesting that our primary screen was sensitised for NCSC defects, and we confirmed 10 novel, 4 previously reported, and 2 functional analogue drug hits in wild-type embryos. Of these drugs, 9/14 and 7/14, respectively, are known to target pathways implicated in osteoarthritis pathogenesis or to cause reduced bone mineral density/increased fracture risk as side effects in patients treated for other conditions, suggesting that our screen enriched for pathways targeting skeletal tissue homeostasis. We selected one drug that inhibited NCSC induction and one drug that inhibits bone mineralisation for further detailed analyses which reflect our initial hypotheses. These drugs were leflunomide and cyclosporin A, respectively, and their functional analogues, teriflunomide and FK506 (tacrolimus). We identified their critical developmental windows of activity, showing that the severity of defects observed related to the timing, duration, and dose of treatment. While leflunomide has previously been shown to inhibit NCSC induction, we demonstrate additional later roles in cartilage remodelling. Both drugs altered expression of extracellular matrix metalloproteinases. As proof-of-concept, we also tested drug treatment of disease-relevant mammalian cells. While leflunomide treatment inhibited the viability of several human NCSC-derived neuroblastoma cell lines coincident with altered expression of genes involved in ribosome biogenesis and transcription, FK506 enhanced murine calvarial osteoblast differentiation and prevented fusion of the coronal suture in calvarial explants taken from Crouzon syndrome mice.

Craniosynostoses

10.6084/m9.figshare.6854483

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Citations (0)

An FDA-Approved Drug Screen for Compounds Influencing Craniofacial Skeletal Development and Craniosynostosis

Molecular Syndromology (2018)

Marian Seda Maartje J. Geerlings Peggy Lim Jeshmi Jeyabalan Ann-Christin Cichon

Neural crest stem/progenitor cells (NCSCs) populate a variety of tissues, and their dysregulation is implicated in several human diseases including craniosynostosis and neuroblastoma. We hypothesised that small molecules that inhibit NCSC induction or differentiation may represent potential therapeutically relevant drugs in these disorders. We screened 640 FDA-approved compounds currently in clinical use for other conditions to identify those which disrupt development of NCSC-derived skeletal elements that form the zebrafish jaw. In the primary screen, we used heterozygous transgenic sox10:gfp zebrafish to directly visualise NCSC-derived jaw cartilage. We noted partial toxicity of this transgene in relation to jaw patterning, suggesting that our primary screen was sensitised for NCSC defects, and we confirmed 10 novel, 4 previously reported, and 2 functional analogue drug hits in wild-type embryos. Of these drugs, 9/14 and 7/14, respectively, are known to target pathways implicated in osteoarthritis pathogenesis or to cause reduced bone mineral density/increased fracture risk as side effects in patients treated for other conditions, suggesting that our screen enriched for pathways targeting skeletal tissue homeostasis. We selected one drug that inhibited NCSC induction and one drug that inhibits bone mineralisation for further detailed analyses which reflect our initial hypotheses. These drugs were leflunomide and cyclosporin A, respectively, and their functional analogues, teriflunomide and FK506 (tacrolimus). We identified their critical developmental windows of activity, showing that the severity of defects observed related to the timing, duration, and dose of treatment. While leflunomide has previously been shown to inhibit NCSC induction, we demonstrate additional later roles in cartilage remodelling. Both drugs altered expression of extracellular matrix metalloproteinases. As proof-of-concept, we also tested drug treatment of disease-relevant mammalian cells. While leflunomide treatment inhibited the viability of several human NCSC-derived neuroblastoma cell lines coincident with altered expression of genes involved in ribosome biogenesis and transcription, FK506 enhanced murine calvarial osteoblast differentiation and prevented fusion of the coronal suture in calvarial explants taken from Crouzon syndrome mice.

Leflunomide

Cranial neural crest

10.1159/000491567

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Citations (17)

Nrf-2 regulation of prion protein expression is independent of oxidative stress

Molecular and Cellular Neuroscience (2014)

Ann-Christin Cichon David R. Brown

10.1016/j.mcn.2014.09.001

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Citations (20)

Oxovanadium-based inhibitors can drive redox-sensitive cytotoxicity in neuroblastoma cells and synergise strongly with buthionine sulfoximine

Cancer Letters (2014)

Owen Clark Inhye Park Alessia Di Florio Ann-Christin Cichon Sarah Rustin

In a wide range of neuroblastoma-derived lines oxovanadium compounds such as bis(maltolato)oxovanadium(IV) (BMOV) are cytotoxic. This is not explained by oxidative stress or inhibition of ion channels. Genotoxicity is unlikely given that a p53 response is absent and p53-mutant lines are also sensitive. Cytotoxicity is inhibited by N-acetyl cysteine and glutathione ester, indicating that BMOV action is sensitive to cytoplasmic redox and thiol status. Significantly, combining BMOV with glutathione synthesis inhibition greatly enhances BMOV-induced cell death. This combination treatment triggers high AKT pathway activation, highlighting the potential functional importance of PTP inhibition by BMOV. AKT activation itself, however, is not required for cytotoxicity. Oxovanadium compounds may thus represent novel leads as p53-independent therapeutics for neuroblastoma.

Buthionine sulfoximine

Mechanism of Action

10.1016/j.canlet.2014.11.039

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Citations (16)

Regulation of Epithelial Differentiation and Proliferation by the Stroma: A Role for the Retinoblastoma Protein

Journal of Investigative Dermatology (2012)

Adam Pickard Ann-Christin Cichon Craig W. Menges D. Patel Dennis J. McCance

Keratinocyte growth factor

Retinoblastoma protein

10.1038/jid.2012.201

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Citations (14)

Author Index

Molecular Syndromology (2019)

Kevin K.L. Lee Philip Stanier Erwin Pauws Oyvind Malde Joseph Libby

10.1159/000496412

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Citations (0)

Title Page / Table of Contents

Molecular Syndromology (2019)

Kevin K.L. Lee Philip Stanier Erwin Pauws Oyvind Malde Joseph Libby

Table (database)

10.1159/000496411

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Abstract 51: Stromal AKT2 controls epithelial invasions

Cancer Research (2012)

Ann-Christin Cichon Adam Pickard D. Patel Dennis J. McCance

Abstract The tumor microenvironment is gaining importance in the regulation of tumorigenesis, invasion and metastasis. Loss of PTEN, a negative regulator of AKT, in stromal fibroblasts results in an increased tumor occurrence in ErbB2 expressing murine mammary tumors. Furthermore, we have shown that activation of AKT in stromal fibroblasts, following loss of the Retinoblastoma Protein (Rb), induces epithelial invasions in organotypic raft cultures, via an increase in Keratinocyte Growth Factor (KGF) expression. In addition, we have shown that loss of the PTEN tumor suppressor in stromal fibroblasts and subsequent activation of AKT, increases invasive potential of Human Papilloma Virus Type 16 E6 and E7 expressing keratinocytes. This is mediated by an increase in KGF expression. There are three isoforms of AKT expressed in human fibroblasts, AKT1, AKT2 and AKT3. By depleting each individual AKT isoform in stromal fibroblasts we have been able to establish that AKT2 is essential in regulating the cross talk between epithelium and stroma, and depletion of stromal AKT2 inhibits invasions. However, loss of stromal AKT2 does not function exclusively through regulation of KGF levels as it activates a second, protective pathway, which is able to counteract the effects of KGF. This protective pathway is mediated by increased Interleukin1 beta levels produced by the fibroblasts. Preliminary data from head and neck cancer specimens show that AKT is activated in stroma of cells associated with tumor but not normal tissue. Future work will determine the AKT dependent pathways that lead to increased KGF and Interleukin1 beta expression as well as how these factors mediate invasions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 51. doi:1538-7445.AM2012-51

AKT2

10.1158/1538-7445.am2012-51

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Inactivation of Rb in stromal fibroblasts promotes epithelial cell invasion

The EMBO Journal (2012)

Adam Pickard Ann-Christin Cichon Anna C. Barry Declan Kieran D. Patel

10.1038/emboj.2012.153

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Citations (32)