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The University of Southampton
Medicine
Phone:
07845 361124
Email:
G.Thomas@soton.ac.uk

Professor Gareth J Thomas BDS, MScD, PhD, FDSRCS, FRCPath, FRSB

Professor of Experimental Pathology, Consultant in Histopathology

Professor Gareth J Thomas's photo

Professor Thomas leads a group that investigates the effect of the tumour microenvironment on tumour development and progression, particularly the role of cancer-associated fibroblasts in regulating immune escape and tumour invasion. The translational element of this work, including biomarker studies and clinical trials, is focused on head & neck cancer. His research group is based within the Faculty of Medicine campus and comprises both clinical and non-clinical scientists. Potential students, post-doctoral scientists or clinician scientists who are interested in joining her group are encouraged to contact Professor Thomas. He is a Consultant Pathologist in University Hospital Southampton NHS Foundation Trust.

As a clinical pathologist I spend a lot of time looking down a microscope at cancers. My research focuses on understanding how the different cells within a tumour interact to affect patient survival, and particularly how cancers escape the immune system and spread. My goal is to translate this research into clinical practice, and ultimately to help patients by improving diagnosis and treatment

Gareth Thomas was appointed to the Chair of Experimental Pathology in 2009. He trained in Oral & Maxillofacial Pathology at University College Hospital, London, gaining his FDSRCS in 1994, MRCPath in 2004 and FRCPath in 2008. He undertook his PhD as an MRC Clinical Fellow at University College London and the Richard Dimblebey Department of Cancer Research, ICRF studying keratinocyte integrin biology (1996-1999). In 2004 he was awarded a 5-year Clinician Scientist Fellowship from the Heath Foundation/Royal College of Pathologists to develop novel alphavbeta6 integrin-directed therapies in head & neck cancer. He was appointed Professor of Oral Pathology and Consultant in Oral and Maxillofacial Pathology at Bart’s and the London in 2007, before being appointed to the Chair of Experimental Pathology in Southampton in 2009.

His key research interest is the investigation of cancer-associated fibroblasts (CAF) in promoting tumour progression; characterising the spectrum of fibroblast heterogeneity in tissues, understanding how different phenotypes are regulated and how these interact functionally with other cell types.  The translational element of this work focuses on developing therapeutic strategies to target CAF clinically as part of cancer treatment.

Qualifications

BDS, University of Wales College of Medicine 1989,
MScD, University of Wales College of Medicine 1995
PhD, University College London 2000

Fellowships

FDSRCS, Royal College of Surgeons (Eng) 1994
MRCPath, Royal College of Pathologists 2004
FRCPath, Royal College of Pathologists 2008
FRSB, Royal Society of Biology 2013

Appointments held

MRC Clinical Training Fellow, Eastman Dental Institute, University College London 1996-1999
Specialist Registrar and Honorary Lecturer, University College London Hospital 2000-2004
Health Foundation/Royal College of Pathologists Senior Research Fellow, Institute of Cancer, Bart’s and the London 2004-2007

Professor of Oral and Maxillofacial Pathology, Bart’s and the London, 2007-2009

Research interests

The role of the tumour microenvironment

The ‘normal’ components of the tumour stroma (including fibroblasts, inflammatory cells, endothelial cells) play a major role in promoting tumour development and progression. This was emphasised strikingly in our large biomarker studies examining oral, oesophageal and colorectal cancer survival, where we found that tumours containing high numbers of myofibroblastic cancer-associated fibroblast (CAF) behaved aggressively and responded poorly to treatment. This clinical association of CAF with poor prognosis has shaped our basic laboratory research which focuses on understanding mechanisms regulating CAF differentiation, investigating CAF phenotypes and functions and developing therapeutic strategies to target CAF clinically. Our aim is to develop a better understanding of CAF subtypes and function in cancers, identifying potential targets that we hope to translate into effective clinical therapies.

This work encompasses a range of techniques, ranging through ‘omic analysis’ of human tissues, including single cell RNA sequencing and molecular spatial analysis, in vitro functional assays, including 3D-organoid and tissue slice models, and in vivo mouse work, including vaccine and checkpoint immunotherapy models, to study translational immunology and therapy resistance.  The work has supported the development of several first in man clinical trials. 

Regulation of CAF differentiation and function: Our recent work on mechanisms regulating myofibroblast differentiation has identified a central role for the reactive oxygen species-generating enzyme, NOX4 in generating a CAF-rich stroma in many different types of cancers, and we have described commonalities linking fibroblast senescence, the DNA damage repair pathway and myofibroblast differentiation, suggesting these are closely related processes.

To investigate CAF functions, we have developed in vitro 3D organoid models and CAF-rich mouse models that recapitulate the morphology of human tumours. Functional work focuses on the effect of CAF on tumour cell invasion and the immune microenvironment. For example, we recently showed that CAF exclude CD8 T-cells from tumours, which results in resistance to different immunotherapies, including anti-cancer vaccination and anti-PD1 checkpoint therapy.  Given that a significant proportion of solid cancers are CAF-rich, this is likely to be a common, mechanism for immunotherapy failure in multiple tumour types.   

Characterising CAF phenotypes and interactions

It is thought that tissue fibrosis in some form or other is responsible for >40% of all deaths, yet fibroblasts remain a poorly characterised, heterogenous cell population, and there are many unanswered questions about this cell. For example, it is not clear how many CAF subtypes exist, how they function, whether they differ between tumours or from where they originate. To investigate these questions, we use single cell RNA sequencing (ssRNASeq) of tissues supplemented with other ‘omic’ approaches such as proteomics and methylation analysis, and combined with multiplexed immunochemistry and in situ mass spectrometry to examine spatial relationships of cells and signalling niches in tissues. We are using these techniques to identify distinct populations of fibroblasts and produce molecular maps of their distribution in tissues.

Translational studies

Mechanistic studies investigating CAF differentiation has led to translational work developing therapeutic strategies to target CAF clinically. Our most advanced work is focused on the NOX4 inhibitor GKT137831 (Setanaxib) developed as an antifibrotic by Genkyotex (Geneva) with whom we have a longstanding collaboration. We have used this inhibitor to successfully reverse the CAF phenotype and overcome CAF-mediated immunotherapy resistance in mouse models. Plans for a clinical trial combining this with anti-PD1 are currently in development. Similarly, our work on other CAF signalling pathways has led to collaborations pharmaceutical companies, including Astrazeneca and Ono Pharmaceuticals both for testing pre-existing drugs and identification of novel CAF targets.

Current clinical studies

Investigation of the molecular and genetic mechanisms promoting head and neck cancer development and progression 2010-2015 (UKCRN 8130; ISRCTN 71276356). Chief Investigator GJ Thomas.

Molecular and genetic mechanisms regulating pancreatic cancer development and progression. 2012-2017 (UKCRN 10180). Chief Investigator GJ Thomas.

PhD Supervision

24 (14 main supervisor; 10 co-supervisor; including 5 MRC Clinical Fellows & 3 CRUK Clinical Fellows)

MDs supervision  - 5 (1 main supervisor; 4 co-supervisor)

Professor Thomas was awarded the Faculty Postgraduate Supervisor Prize in 2012.

Group members have been awarded 12 local, 19 national and 6 international research prizes.

 

Figure shows tumour cells invading an organotypic culture
Figure 1 Microenvironment projects
Figure shows a co-culture of alphavbeta6-expressing tumour cells (red) and smooth muscle actin-expressing myofibroblasts (green). Cell nuclei are shown in blue.
Figure 2 Microenvironment projects

Research group

Cancer Sciences

Affiliate research group

Cancer Sciences Research group

Faculty of Medicine

DI Faculty of Medicine Tissue Bank

Academic Lead Research Governance

Academic Lead for Cellular Pathology, UHS NHS Foundation Trust

Southampton Lead for CRUK Accelerator in Digital Pathology

 
National responsibilities

NIHR Senior Fellowship Panel (2019 –)

NC3R CRACK-IT Panel (2019 –)

Chair Pathological Society Research Sub-Committee (2018 -)

Royal College of Pathologists Research Committee (2018 –)

Pathological Society of Great Britain Molecular Sub-Committee (2018 -)

NCRI Clinical Trials Pathology Advisory Group (CT-PAG) Steering Committee (2017 -)

NCRI Cellular & Molecular Pathology (CM-path) Initiative, Workstream Lead (2016-19)

Cancer Research UK Experimental Medicine Expert Review Panel (2015 – 19)

NIHR Career Development, Senior Research and Transitional Research Fellowships Panel (2017-19)

NCRI Molecular Biomarkers Advisory Group (2015-17)

The Pathological Society of Great Britain and Ireland Committee (2015 -)

NC3R Expert Panel Member - New technologies to support the 3Rs in cancer research (2017)

NCRI Molecular Biomarkers Advisory Group (2015-17)

Committee Member of The Pathological Society of Great Britain (2014-18)

ECMC Cellular and Molecular Pathology Network Group Steering Committee (2014-16)

NCRI Biomarkers and Imaging Clinical Studies Group (2012-15)

Chair of Molecular Biology Expert Panel. Research Council of Norway (2011-13)

NCRI Head and Neck Cancer Clinical Studies Group (2009-2016)

National Grant reviewer

Medical Research Council, Wellcome Trust, Cancer Research UK, NIHR, Academy of Medical Sciences, NC3R, Association of International Cancer Research (AICR), Yorkshire Cancer Research, Dystrophic Epidermolysis Bullosa Research Association (DEBRA), The Humane Research Trust and the Breast Cancer Campaign,

International Grant reviewer

Norwegian Research Council, Dutch Cancer Society, Italian Association for Cancer Research, Belgium Foundation against Cancer, French National Alliance for Life and Health Sciences (AVIESAN), Netherlands Organisation for Scientific Research

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Professor Gareth J Thomas
University of Southampton, Faculty of Medicine Cancer Sciences Unit, Somers Building, MP 824 Tremona Road Southampton SO16 6YD Tel: 07845 361124

Room Number: SGH//MP824

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