Advances in Cell and Tissue Culture - Adrian Biddle

Speaker Spotlight: Adrian Biddle

Dr Adrian Biddle

Advances in Cell and Tissue Culture - Adrian BiddleDr Biddle is an NC3Rs Research Fellow in the Centre for Cell Biology and Cutaneous Research. His research interest is in non-genetic cellular heterogeneity in cancer, and how such heterogeneity might be responsible for therapeutic resistance. He is particularly interested in the plasticity of heterogeneous cancer cell sub-populations, the molecular mechanisms driving plasticity, and how plastic sub-populations can be modelled in vitro.

In vitro modelling of cancer stem cell therapeutic responses for drug discovery

Session: Developments within In Vitro Cancer Research
Author: Adrian Biddle, Blizard Institute, Queen Mary University of London, London, UK.

Abstract: The aim of our research is to develop human cell culture models that have demonstrable relevance to human cancer and can replace mouse cancer models to enable more efficient drug discovery. Using an oral cancer cell line model, we have demonstrated that cancer stem cells (CSCs) drive tumour metastasis by undergoing epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) to switch between epithelial and mesenchymal sub-populations (Biddle et al., 2011). We have further demonstrated heightened therapeutic resistance and metastatic potential of a novel CSC sub-population in oral cancer that exhibits a hybrid epithelial-mesenchymal phenotype and has a CD44highEpCAMlowCD24+ cell surface marker profile (Biddle et al., 2016). This presents an attractive target for new therapies aimed at overcoming tumour therapeutic resistance and metastatic proclivity. We have now developed a method to enrich these CSCs in cell culture for therapeutic development (Biddle et al., 2016) and, using this method, we are able to test candidate therapeutic compounds and further dissect the molecular mechanisms driving the behaviour of these hybrid CSCs.

The demonstration that CSC sub-populations can be modelled using cell lines in vitro provides an opportunity for the efficient discovery of novel therapeutic strategies. However, there is currently some uncertainty over the relevance of cell culture models to human cancer, and this has driven an increase in the use of mouse cancer models. New models that possess greater physiological relevance whilst retaining the experimental tractability of in vitro models are therefore required. We are currently developing an in vitro 3D model system that can incorporate both human cancer cell lines and explanted fresh tumour material, and testing its ability to accurately model human tumour biology and therapeutic response. We are also building a validation model using FFPE tumour sections to comprehensively validate the findings from our human cell culture model.
References: Biddle, A., Liang, X., Gammon, L., Fazil, B., Harper, L. J., Emich, H., Costea, D. E., and Mackenzie, I. C. (2011). Cancer stem cells in squamous cell carcinoma switch between two distinct phenotypes that are preferentially migratory or proliferative. Cancer Res 71, 5317-5326.

Biddle, A., Gammon, L., Liang, X., Costea, D. E., and Mackenzie, I. C. (2016). Phenotypic Plasticity Determines Cancer Stem Cell Therapeutic Resistance in Oral Squamous Cell Carcinoma. EBioMedicine 4, 138-145.

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Advances in Cell and Tissue Culture - Phil Jeffrey

Confirmed Session Chair – Dr Phil Jeffrey

Dr Phil Jeffrey

Advances in Cell and Tissue Culture - Phil JeffreyPhil Jeffrey Ph.D. is an independent consultant with over 35 years’ experience in the pharmaceutical industry and a successful track record in drug discovery from early lead optimisation through to clinical proof of mechanism and proof of concept.  He has worked across a wide variety of therapeutic areas including; auto-immunity, inflammation, CNS, anti-infectives, epigenetics, cardiovascular and most recently rare diseases at Pfizer, where he was responsible for developing translational science strategies across all stages of the portfolio.

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Prior to joining Pfizer, Phil worked at GlaxoSmithKline (GSK) and in addition to leading the Quantitative Pharmacology and Translational Sciences group he was instrumental in developing approaches to preclinical pk/pd modelling and simulation, early human clinical dose predictions and understanding drug disposition in the CNS.  Before joining GSK, Phil worked at SmithKlineBeecham and The Upjohn Company leading and supporting early phase drug discovery projects for both US and UK research programmes.

Phil has a PhD in pharmacokinetics and drug metabolism from the University of Sheffield and is an Honorary Professor at the William Harvey Research Institute, Queen Mary University of London.  He is a member of the editorial board for the British Journal of Pharmacology and Xenobiotica and has authored/co-authored over 50 peer reviewed papers and 4 book chapters.

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Advances in Cell and Tissue Culture - Joan Abbott

Confirmed Keynote Speaker: Professor Joan Abbott

Professor Joan Abbott

We are delighted to announce that Professor Joan Abbott (EMIRITUS PROFESSOR OF NEUROSCIENCE, KINGS COLLEGE LONDON) will give a keynote presentation within the "Building Better Blood Brain Barrier models" session at ACTC Cambridge.

 

Research Summary

Our chief interest is the ‘multi-tasking’ blood-brain barrier (BBB). The brain capillary endothelium forming the BBB regulates molecular traffic between band brain, and protects the brain from potentially harmful substances circulating in the blood. Understanding the complexity of BBB physiology helps in the design of modern CNS drug therapies. Many neuropathologies involve BBB breakdown or dysfunction – treating the barrier could help reduce the severity of neurodegeneration and aid repair.

DEVELOPING GOOD IN VITRO MODELS OF THE BBB


We have optimised several cell culture models of the brain endothelium that permit study of a range of functional activities of the BBB, and may have applications in screening drugs for permeability across the BBB.

TRANSPORT FUNCTIONS OF THE BBB AND FLOW OF INTERSTITIAL FLUID


The BBB has uptake and efflux carriers mediating bi-directional molecular transport. We are examining transporters that could be used to deliver drugs to the brain, and others (efflux transporters) that impede drug entry. We are also studying BBB ion transport, and its key role in the formation and regulation of brain interstitial fluid (ISF). We are mapping the routes for ISF flow, with application in programmes designed to deliver therapeutic agents to the brain. Disturbances of ISF production and flow may be involved in several brain disorders including stroke and tumours.

CELL:CELL SIGNALLING AT THE BBB


The ‘BBB phenotype’ develops in brain endothelium under the inductive influence of closely associated cell types, especially astrocytic glial cells. The mature BBB appears to be modulated physiologically by signals from glia and neurons, and possibly other cell types, allowing coordination of the ‘neurovascular unit’. We are using cell culture models and fluorescence imaging to determine the receptors present, and their role in cell:cell signalling. Many of the endothelial receptors we have identified cause a rise in intracellular calcium – a possible first step in signal transduction pathways by which glial cells (and neurons) could influence endothelial physiology (tightness, transport function, metabolism).

BBB MODULATION IN PATHOLOGY


We have a number of collaborative projects on the role of BBB dysfunction in neurological disorders, including multiple sclerosis. The aim is to understand the mechanisms by which the barrier may be impaired, and the implications for the neurological condition. We are also exploring therapeutic strategies that may reduce BBB damage and hence limit the severity of brain disorders.

DRUG DELIVERY ACROSS THE BBB


By careful examination of the routes for molecular movement across the BBB we are developing ‘predictive rules’ to guide the design of drug compounds to target or avoid the brain. So far this works best for lipid soluble compounds passively diffusing across the endothelial lipid membranes. The next step will be to incorporate understanding of uptake and efflux transporter function. We are also working on novel methods for delivering ‘problem drugs’ (large or polar molecules) including use of nanoparticle delivery systems, and transient opening of the BBB. Our successful ‘BBB Consortium with Industry’ is now operating in ‘Club’ mode: organising meetings, advising on new developments, and setting up joint research projects (enquiries welcome)

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Advances in Cell and Tissue Culture - Fran Balkwill

Confirmed Keynote Speaker: Professor Fran Balkwill

Professor Fran Balkwill

Advances in Cell and Tissue Culture - Fran Balkwill
We are delighted to announce that Professor Fran Balkwill OBE (CENTRE LEAD, CENTRE FOR CANCER AND INFLAMMATION /INSTITUTE OF BIOENGINEERING DIRECTOR OF RESEARCH STRATEGY, QUEEN MARY UNIVERSITY LONDON) will give a keynote presentation within the "Developments Within In Vitro Cancer Research" session at ACTC Cambridge.

RESEARCH INTERESTS

  1. The Tumour Microenvironment
  2. Inflammatory cytokines and chemokines in the tumour microenvironment
  3. 'Ovarian' cancer with a focus on high grade serous and clear cell subtypes
  4. Public engagement with biomedical science and science policy

 

Research Summary

I am Professor of Cancer Biology at Barts Cancer Institute, Queen Mary University of London, where I lead the Centre for Cancer and Inflammation and the Cytokine and Cancer group within that Centre. I study the links between cancer and inflammation and research ways of translating this to clinical trial.

In 2006, I was made a Fellow of the Academy of Medical Sciences, being elected a member of its Council later in the same year. I am a frequent plenary and keynote speaker at international meetings, such as Gordon and Keystone conferences and the American Association for Cancer Research (AACR).

I am also actively involved in communication of science to non-specialist audiences, especially young people. I have written thirteen science books for children on cell and molecular biology, with titles such as Enjoy Your Cells and The Egg and Sperm Race.

I am the Director of the Centre of the Cell, a biomedical science centre for children, educational website, and widening participation and outreach project in Whitechapel. The website was launched in March 2007 and the physical Centre opened in September 2009. As of October 2014 there have been over 85,000 participants in Centre of the Cell activities (www.centreofthecell.org).

I am a non-parliamentary board member of the Parliamentary Office of Science and Technology, POST and Chair of Understanding Animal Research (UAR). I am on the Scientific Advisory Committee of Breakthrough Breast Cancer and I was awarded an OBE in the 2008 Queen's Birthday Honours list.

My research is focused on the links between cancer and inflammation, being especially interested in translating knowledge of cancer biology into new biological treatments for cancer and in the role that inflammatory cytokines play in cancer promotion.

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Advances in Cell and Tissue Culture - Mike Philpott

Confirmed Keynote Speaker: Professor Mike Philpott

Professor Mike Philpott


We are delighted to announce that Professor Mike Philpott (PROFESSOR OF CUTANEOUS BIOLOGY, QUEEN MARY UNIVERSITY LONDON) will give a keynote presentation within the "More Human Relevant ALI Models" at ACTC Cambridge.

Professor Philpott obtained a BSc in Marine Biology and Biochemistry from the University of Wales, Bangor in 1986 and his D.Phil. from the University of Oxford in 1989.  The title of his thesis was ‘Studies on isolated hair follicles’ from which he published on the in vitro culture and growth of human hair follicles now referred to as the ‘Philpott model’. This paper reported, for the first time, the successful isolation and culture of human hair follicles and showed that hair follicles could be kept alive in the laboratory and continue to produce hair at the same rate as that produced while still in the scalp. The Philpott model has allowed scientists to carry out many experiments previously impossible to investigate the effects of growth regulatory factors on human hair growth.  He continued his research into hair follicle biology at the University of Cambridge from 1989 until 1994. In 1994 he joined Unilever Research, leaving in 1996 to take up a lectureship at Barts and The London SMD.  He was appointed senior lecturer in 1999, Reader in 2003 and Professor of Cutaneous Biology in 2005. He became Centre lead for Cutaneous Research in 2006.

Member British Society for Cell Biology (BSCB), European Society for Investigative Dermatology (ESDR)and European Hair Research Society (EHRS). Honorary Fellow Trichological Society.

 

Research Summary

We are investigating the role of Gli2 in protecting human keratinocytes from UVB induced apoptosis as well as its role in cell ploidy. We are also investigating the role of Gli2 in the canonical and non canonical Wnt signalling as well as the role of Gli2 in epithelial mesenchymal transition (EMT). In Basal Cell Carcinoma we are investigating the role of paracrine Hedgehog (HH) signalling between the stroma and epithelium and the role of oncogene induced senescence (OIS). We have made stable Gli1 and Gli2 expressing cell lines as well as PTCH knockdowns (in both N/TERT-1 and NEB-1) keratinocytes and these are being used as in vitro models to investigate the HH pathway in skin cancer and in conjunction with BCC derived stromal cells to develop novel in vitro models of BCC as alternatives to animals. We are also investigating the role of oxidative stress, Reactive Oxygen Species (ROS) and Dihydrotestosterone (DHT) on balding hair follicle senescence and the role of TGF-β. Studies are also being carried out to investigate the role of skin steroid synthesis in both the hair follicle in relation to hair loss and in eczema and psoriasis.

Recent and ongoing research projects:

  1. The role of Gli in human skin cancer
  2. In vitro modelling of skin carcinogenicity and human Basal cell carcinoma
  3. The role of oxidative stress in human hair growth
  4. Steroidogenesis in skin
  5. In vitro modelling of the human eccrine sweat gland

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Advances in Cell and Tissue Culture - David Hay

Confirmed Keynote Speaker: Professor David Hay

Professor David Hay

We are delighted to announce that Professor David Hay (Group Leader and Professor of Tissue Engineering, University of Edinburgh) will give a keynote presentation within the "Exploring New Trends in Stem Cell Research Session" at ACTC Cambridge.

David has worked in the field of stem cell biology and differentiation for over fifteen years. David and his team have highlighted the important role that pluripotent stem cells have to play in modelling human liver biology ‘in a dish’ and supporting failing liver function in vivo. The impact of this work has led to a number of peer reviewed publications, regular appearances at high profile conferences and three start-up companies.

Brief Biography

  • Group leader of the Pluripotent Stem Cell Hepatocyte Development team
  • Expert in hepatocyte differentiation and in vitro modelling
  • Over 10 years experience in pluripotent stem cell biology
  • Experience of spin-out company formation
  • PhD 2000 and BSc (Hons) 1996, University of St Andrews, UK

2017 Publications

Erratum to: Modelling foetal exposure to maternal smoking using hepatoblasts from pluripotent stem cells.Lucendo-Villarin, Baltasar, Filis Panagiotis, Swortwood Madeleine J., Huestis Marilyn A., Meseguer-Ripolles Jose, Cameron Kate, Iredale John P., O'Shaughnessy Peter J., Fowler Paul A., and Hay David C. , Arch Toxicol, 2017 Oct 03, (2017)
A Drug-Induced Hybrid Electrospun Poly-Capro-Lactone: Cell-Derived Extracellular Matrix Scaffold for Liver Tissue Engineering.Grant, Rhiannon, Hay David C., and Callanan Anthony , Tissue Eng Part A, 2017 Jul, Volume 23, Issue 13-14, p.650-662, (2017)
Modelling foetal exposure to maternal smoking using hepatoblasts from pluripotent stem cells.Lucendo-Villarin, Baltasar, Filis Panagiotis, Swortwood Madeleine J., Huestis Marilyn A., Meseguer-Ripolles Jose, Cameron Kate, Iredale John P., O'Shaughnesy Peter J., Fowler Paul A., and Hay David C. , Arch Toxicol, 2017 May 16, (2017)
Mechanistic evaluation of primary human hepatocyte culture using global proteomic analysis reveals a selective dedifferentiation profile.Heslop, James A., Rowe Cliff, Walsh Joanne, Sison-Young Rowena, Jenkins Roz, Kamalian Laleh, Kia Richard, Hay David C., Jones Robert P., Malik Hassan Z., et al. , Arch Toxicol, 2017 Jan, Volume 91, Issue 1, p.439-452, (2017)
Stem cell-derived models to improve mechanistic understanding and prediction of human drug-induced liver injury.Goldring, Christopher, Antoine Daniel J., Bonner Frank, Crozier Jonathan, Denning Chris, Fontana Robert J., Hanley Neil A., Hay David C., Ingelman-Sundberg Magnus, Juhila Satu, et al. , Hepatology, 2017 Feb, Volume 65, Issue 2, p.710-721, (2017)
Defined and Scalable Generation of Hepatocyte-like Cells from Human Pluripotent Stem Cells.Wang, Yu, Alhaque Sharmin, Cameron Kate, Meseguer-Ripolles Jose, Lucendo-Villarin Baltasar, Rashidi Hassan, and Hay David C. , J Vis Exp, 2017 Mar 02, Issue 121, (2017)

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