Professor John F Marshall

CRUK GC BUTTON

Professor John F Marshall

BSc (Hons), MPhil, PhD
Centre: Tumour Biology
Professor of Tumour Biology
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QMUL Directory


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).

Research Details

Integrins deliver spatiotemporal signals into cells after 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 (e.g. endothelial cells) are required for tumour progression. For several years we have concentrated on the role of integrin αvβ6. This epithelial-specific integrin is not detectable on most normal tissues but may be upregulated during tissue remodelling (e.g. chronic wounds, cancer).

Our activities include pathology, biology and translation studies:

Pathology

Pathology drives our direction in biology. In our study of about 3,000 breast cancers, we have found that αvβ6 was expressed strongly by 17% cases and was associated significantly with reduced overall survival, particularly if HER2 was also upregulated.

In separate studies, we established that 90% of pancreatic cancers express αvβ6 whereas normal pancreas expresses very little or 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 studies 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. As αvβ6 activates TGF6 and as this in turn can promote formation of cancer associated fibroblasts (CAFs) that help cancers develop, we have now developed significant interests in studying fibroblast biology in tumour progression.

Translation

Integrin αvβ6-directed imaging and therapy for cancer are major goals.

We have identified a peptide (A20FMDV2) that is highly specific for αvβ6. Since αvβ6 promotes TGF6-dependent lung fibrosis it was used by GSK in idiopathic pulmonary fibrosis studies (NCT02612051).

Recently, in collaboration with Imanova, our IMPACT trial is using 18F-A20FMDV2 for imaging solid cancers. In separate studies we identified αvβ6-inhibitory antibodies that we hope will enter clinical trials.

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.

Using bladders from carcinogen treated rats, we found 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 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 then 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 Epidermolysis Bullosa 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 Breast Cancer Now 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 strongly by the corresponding normal tissue, success of any of our therapeutic programmes could translate to treatments for many of these patients.

I hope and expect the next few years to be very exciting.

Funding

 Summer 2017 - 2022 Cancer Research UK (Grand Challenge Scheme 2016) Consortium leader: Dr Josephine Bunch, NPL
BCI Principal Investigator: Prof John F Marshall
"A complete cartography of cancer using multi-scale molecular imaging"
Total Funding: £16,000,000
BCI funding: £1,651,035
Oct 2017 - Sep 2021 BBRSC Industrial CASE  "Use of CRISPR/Cas9 to dissect endocytosis and trafficking in lung epithelia"
£120,000
 Feb 2017 - Sep 2019 Pancreatic Cancer Research Fund  "Development of a new peptide-drug conjugate for treating avß6-positive pancreatic ductal adenocarcinoma (PDAC)."
£179,982
 Jan 2016 - Dec 2018  Barts Charity "IMETAB6 (Imaging MEtastatic breast cancer by TArgeting integrin alpha-v Beta-6) trial"
£464,413
Apr 2016 - Mar 2018 Cancer Research UK "Development of novel peptide-petaibol chemotherapeutics for the therapeutic targeting of avß6-expressing cancers"
Ref 21624, CRUK Ref NZPeptide C15532/A21624
£199,383
Nov 2014 - Dec 2016 IMANOVA Chinical trial pilot: "IMaging pilot study of the avß6 integrin radiotracer [18F]A20FMDV2 in PAtients with solid Cancer Types (IMPACT)"
£70,000
October 2014 Cancer Research UK "Development of Imaging and therapy of avß6 in lung cancer"
£200,000
Aug 2015 - Jul 2016 British Lung Foundation "Investigating the biology of avß6 in lung cancer"
£29,000
Aug 2014 - Jul 2016 Rosetrees Trust "The role of avß6 in lung cancer"
£20,000
Apr 2012 - Mar 2013 Pancreatic Cancer Research Fund Extension to current project (1 year)
£27,530
2013 Cancer Research UK "Systematic development of the anti-avß6 imaging peptide A20FMDV2 for use as an anti-cancer therapeutic"
£96,650
2013 AstraZeneca UK Limited * "Use and development of a novel higher throughout 3D organotypic invasion assay for assessing the effects of stromal fibroblasts on drug cvtotoxicity"
£26,124
2013 Medical Research Council "MRI to reduce and refine the use of mice in cancer and trauma research"
£342,469
2013 BBSRC (*As above)
£101,520
Oct 2012 Cancer Research UK Co-investigator with Prof. J Louise Jones
"Integrin regulation of invasion in breast Cancer Research"
£90,000
2012 Breast Cancer Campaign "Novel transgenic mouse models for identifying biomarkers of avß6/HER2-dependent breast cancer"
£221,817
2012 BBSRC * "The role of integrins in the regulation of fibroblast activity and activation"
£100,173
2012-2015 Pancreatic Cancer Research Fund "Using transgenic mourse models to develop integrin avß6-targetted therapy of pancreatic cancer"
£179,992
2011-2013 DebRA Co-invesigator with Edel O'Toole: "Dissecting the role of basement membrane components in a xenograft model of cutaneous SCC"
£114,960

Key Publications

Whilding LM, Parente-Pereira AC, Zabinski T, Davies DM, Petrovic RM, Kao YV, Saxena SA, Romain A, Costa-Guerra JA, Violette S, Itamochi H, Ghaem-Maghami S, Vallath S, Marshall JF, Maher J. Targeting of Aberrant αvβ6 Integrin Expression in Solid Tumors Using Chimeric Antigen Receptor-Engineered T Cells. (2017) Mol Ther. 25(1):259-273. PMID: 28129120

Moore KM, Thomas GJ, Duffy SW et al. Therapeutic targeting of integrin αvβ6 in breast cancer. (2014) J Natl Cancer Inst vol. 106, (8) PMID: 24974129

Allen MD, Thomas GJ, Clark S et al. Altered microenvironment promotes progression of preinvasive breast cancer: myoepithelial expression of αvβ6 integrin in DCIS identifies high-risk patients and predicts recurrence. (2014) Clin Cancer Res (2) 344-357. PMID: 24150233

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. (2010) J Path. 222:52-63. PMID: 20629113


Further Publications

For additional publications, please click here.


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).

External Activities

  • Member of the Scientific Advisory Board for DebRA (Dystrophic Epidermolysis Bullosa Research Association)
  • Co-organiser of the VOICE course for training Cancer Patient Advocates in science
  • Organiser of the BCI STARS (Science Training for Aspiring Research Scientists) programme for Year 12 and 13 school students

(See the News tab for more information)

News

Overview of BCI STARS courses.

  • September 2017: Speaker for the British Society of Matrix Biology meeting
  • March 2017: Speaker at the International Association for Dental Research meeting, San Francisco, USA
  • February 2017: Announced as part of the Bunch team, together with Dr Becki Pike in our Flow lab, working on a 'Google Earth of Cancer' in the CRUK Grand Challenge
  • February 2017: Shortlisted for the QMUL Public Engagement "Inspire" Award
  • January 2017: Speaker at the Fibronectin, Integrin and Related Molecules Gordeon Conference, Ventura, USA
  • 2016: BCI STARS programmes opened at QMUL's Blizard Institute and Kings College London
  • October 2015: Speaker at BCI's ECMC Symposium, on taking a drug from the bench to clinical trials
  • September 2015: Lectured at third VOICE course run at BCI
  • July 2015: Third BCI STARS programme successful - invited to Downing Street again and KCL to run a programme
  • January 2015: confirmation that our anti-αvβ6 antibody 264RAD will be entering clinical trials soon
  • October 2014: Wear It Pink video for Breast Cancer Campaign
  • September 2014: Second VOICE course run successfully
  • July 2014: Q&A with Dr Kate Moore for Breast Cancer Campaign
  • July 2014: New paper in JCNI on αvβ6 as biomarker and promising Ab/chemotherapy combination treatment
  • January 2014: Visit to Downing Street for acknowledgement of role in STARS programme
  • October 2013: The first STARS course was completed successfully
  • September 2013: VOICE pilot course well-received - funding secured for 2014
  • July 2013: Completed the West Highland Way PCRF fundraising walk
  • July 2013: Oversaw the BCI Postgraduate Day 2013
  • July 2013: Work from the Marshall lab presented at the Beatson conference
  • May 2013: CRUK drug discovery grant awarded
  • March 2013: PCRF grant for pancreatic cancer project awarded
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