Dr John Marshall
Research Interests
Dr John Marshall's main research themes are in: Adhesion and Integrins, Breast Cancer, Cancer Cell Biology, Imaging & Nuclear Medicine, Metastasis and Invasion and Pancreatic Cancer
For over 25 years I have studied the biology of tumour invasion with a particular interest in the roles of the adhesion molecules expressed on the cell surface that mediate this process. Our group concentrates on the study of integrins that are the principal family of adhesion molecules that mediate interaction between cells and the extracellular matrix (ECM). Integrins deliver spatiotemporal signals into cells subsequent to attachment to ECM proteins. These signals determine whether cells differentiate, move, remain stationary, secrete proteases, invade or deliver a combination of such signals. The activity of specific integrins on cancer cells and tumour-promoting elements of the microenvironment (eg endothelial cells) are required for tumour progression. For several years we have concentrated on the role of αvβ6. This epithelial-specific integrin is not detectable on most normal tissues but may be upregulated during tissue remodelling (eg chronic wounds, cancer). Our activities include pathology, biology and translation studies.
Pathology: Pathology drives our direction in biology. In our study of over 3,000 breast cancers, we have found that αvβ6 was expressed strongly by 15-17% cases and was associated significantly with reduced overall survival, particularly if HER2 was also upregulated. In separate studies, we established that over 60% of pancreatic cancers express αvβ6 whereas normal pancreas expresses none. Thus αvβ6 is an important new therapeutic target in many cancers. By understanding its biology we hope to develop novel therapies.
Biology: To improve study of invasion, we re-developed, and made quantitative, a 3-dimensional organotypic invasion assay that better reflects tumour: stroma interactions. This assay now is used by invasion labs globally. We were the first to show that αvβ6 promoted carcinoma invasion and did so, in part, by upregulating proteases that could degrade the ECM offering an explanation for the clinical observations. We also continue to identify novel intracellular regulators of αvβ6 activity including COX2, psoriasin and HAX1.
Translational: αvβ6-directed imaging and therapy for cancer is almost a reality. We have identified a peptide (A20FMDV2) that is highly specific for αvβ6 that we used as a radiotracer for high resolution imaging of αvβ6-positive (i.e. potentially more aggressive) cancers. Clinical trials with A20FMDV2 should commence Jan 2013. With collaborators we have also developed human antibodies to αvβ6 that also we are developing for therapy.
Profile
My career in research science began in the Tissue-Interactions Laboratory of Imperial Cancer Research Fund (now Cancer Research UK) in January 1983. I learned to develop bladder organotypic gels, separating the urothelium from the underlying stroma and recombining them as required. By using bladders from carcinogen treated rats it was determined that the stroma was the more powerful reservoir of pro-tumourigenic development than the epithelium. Others in the lab identified stromal fibroblasts as a key component. Given that the major site for progress in understanding tumour biology is the Tumour Microenvironment this initial 2 years gave me an intellectual and practical head-start that I still use in my research today.
I moved within ICRF to study Invasion and Metastasis with Ian Hart in 1984. I spent 6 years developing Phthallocyanine Photosensitizers for laser activated tumour therapy and during this time studied for an MSc in Medical Immunology (University of London) and also an MPhil before moving onto studying adhesion. I then studied integrins in melanoma providing one the first comprehensive studies of the numerous integrins that melanoma cells upregulate as they transform from melanocytes. Specific study of uveal melanomas (of the eye) revealed the discovery of a previously uncharacterised integrin, αvβ1. On the same day I realised my discovery, a paper in Nature published the discovery of αvβ1, followed by another in Science within a week. The Melanoma integrin work formed the basis of my PhD.
I moved from melanoma to carcinoma in 1998. I co-supervised of a PhD student whose work resulted in the first description of the epithelial-specific αvβ6 as a pro-invasive integrin that regulated matrix-metalloproteinases. Since that time my team has largely concentrated on this integrin, using it as a paradigm for the study of integrin-dependent pro-invasive biology. Several groups, including our own, have shown clearly that αvβ6 is not expressed by normal tissues but is upregulated in many carcinomas where its expression correlates with extremely poor survival. Thus our studies are designed to dissect the cell and molecular biology of αvβ6 in order to develop novel therapies.
The Centre for Tumour Biology arrived at Barts in August 2006. Since 2007 I have been designing and teaching Research Skills and Sciences on 2 MSc courses among other teaching for QMUL. In that same time we have developed αvβ6-specific targeting agents some of which are being developed for clinical trials.
In the last few years I have been privileged to work closely with DebRA. Patients with recessive dystrophic EB have a 70-fold increased risk of skin cancer and, unlike in non-EB patients, these, mostly αvβ6-positive, cancers metastasise and kill most patients. More recently I have begun to work with the Breast Cancer Campaign (BCC) and the Pancreatic Cancer Research Fund (PCRF), in part, because fatal cancers in these patients also often expressed αvβ6 strongly. Since αvβ6 is not expressed by the corresponding normal tissue, success of any of our therapeutic programmes could translate to treatments for many of these patients. So I hope and expect the next few years to be very exciting.
Funding
Awarding Body:MRC
Principal Investigator: John F Marshall
Establishing efficacy and molecular mechanisms of integrin αvβ6 -directed human-antibody therapy of cancer
Total funding £323,800 Jan 2009-Dec2011
Awarding body: Breast Cancer Campaign
Principal Investigators: Louise Jones, Co-applicant John F Marshall
Functional and clinical significance of loss of the tumour-suppressor MMP-8 in myoepithelial cells of DCIS (PhD fellow)
Total Funding £109,280 Feb 2009-Jan 2012
Awarding body: Pancreatic Cancer Research Fund
Principal Investigator: John F Marshall
Development of imaging and therapy of pancreatic cancer by targeting the integrin αvβ6
Total funding £121,640, Jan 2009-Dec 2011
Awarding body: Pancreatic Cancer Research Fund
Principal Investigator: John F Marshall
Development of imaging and therapy of pancreatic cancer by targeting the integrin αvβ6
Total funding £121,640, Jan 2009-Dec 2011
Awarding Body: MRC
Principal Investigator: Gisli Jenkins. Co-investigator: John F Marshall
The evaluation of of the avb6 integrin as a biomarker and therapeutic target for idiopathic pulmonary fibrosis.
Total funding: £419,472 for period 1.12.09-30.11.12
Awarding body: DebRA
Principal Investigator: Edel O’Toole. Co-investigator: John F Marshall
Dissecting the role of basement membrane components in a xenograft model of cutaneous SCC.
Total Funding: £114,960 June 2011-May 2013
Key Publications
Gaggioli C, Hooper S, Hidalgo-Carcedo C, Grosse R, Marshall JF, Harrington K and Sahai E. Fibroblast led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. 2007 Nature Cell Biol. 9:1392-1400. 18037882
Gagnon MK, Hausner SH, Marik J, Abbey CK, Marshall JF, Sutcliffe JL. High-throughput in vivo screening of targeted molecular imaging agents. 2009 Proc Natl Acad Sci U S A. 106:17904-9. 19815497
Saha A, Ellison D, Thomas GJ, Vallath S, Mather SJ, Hart IR and Marshall JF. High resolution in vivo imaging of breast cancer by targeting the pro-invasive integrin αvβ6 J Path 2010 222:52-63. 20629113
Morgan MR, Jazayeri M, Ramsay AG, Thomas GJ, Boulanger MJ, Hart IR, Marshall JF. Psoriasin (S100A7) associates with integrin β6 subunit and is required for αvβ6-dependent carcinoma cell invasion. Oncogene. Dec 2010. 21132011
Further Publications
For additional publications, please click here.
Research Group
β6 Biology Group
- Delphine M Lees PhD, Postdoctoral Research Fellow
- Kate Moore PhD, Postdoctoral Research Fellow
- Adrian T Churchman PhD, Postdoctoral Research Fellow
- Y. K. Stella Man PhD, Postdoctoral Research Fellow
- Sabari Vallath MSc, PhD Student
- Chia-Yu Chen MSc, PhD
External Activities
- Member of the Scientific Advisory Board for Breast Cancer Campaign
- Member of the Scientific Advisory Board for DebRA (Dystrophic Epidermolysis Bullosa Research Association)
- Committee Member of UK Adhesion Society
- Sub Editor for Anticancer Research
- Sub Editor for Cell Communication and Adhesion
- Chairman of Health and Safety Sub-Committee for School of Medicine and Dentistry
News
- Patents for A20FMDV2 are filed in Europe, North America, Japan (2008)
- Aura Bioscience (USA) are granted a licence from Cancer Research Technologies to develop αvβ6-specific peptide A20FMDV2 for Targetting Therapeutic Nanoparticles. (November 2008)
- New Agents Committee of Cancer Research UK grant support of development of A20FMDV2 for Radio-imaging of Cancer (Dec 2010)
