Professor Gillian Tozer, PhD
Department of Oncology & Metabolism
The Medical School
Beech Hill Road
Tel: +44 (0)114 215 9028
Fax: +44 (0)114 271 3314
I joined the University of Sheffield as Professor of Tumour Biology in 2004 from the Gray Cancer Institute in London. I started my research career in radiation biology, which stimulated an interest in the tumour microenvironment. After a first degree in Biology and Physics at Keele University and an MSc in Radiation Biology at the University of London, I carried out my PhD in Radiation Biology at St Thomas´ Hospital, University of London, completing in 1982. Following a post-doctoral research fellowship at Harvard Medical School in Boston, USA, I moved to the MRC Cyclotron Unit at the Hammersmith Hospital, London. In 1989, I joined the Cancer Research Campaign (now CR-UK) funded Gray Laboratory (later Gray Cancer Institute) in London.
I am currently PI and co-PI on two CR-UK funded programme grants and I am research lead for the Department of Oncology. I have several other on-going research projects funded from a number of sources, including industry, and I am engaged in various external activities, including membership of advisory and grant reviewing committees.
My research interests are concerned with the tumour microcirculation and microenvironment and their roles in tumour progression, therapeutic vascular targeting and development of clinically applicable imaging bio-markers for vascular targeted therapeutics.
I am primary or second supervisor for a number of PhD students. I currently lecture on the Medical School´s Molecular Medicine MSc course and the University of London´s Radiation Biology MSc course. My group hosts medical students for 6-week research placements and for longer research projects to gain a BMedSci qualification, as well as MSc students and clinical fellows.
- Tumour Microcirculation
This programme of work is funded by Cancer Research UK and is concerned with the maturation phase of angiogenesis as it relates to the tumour microcirculation and its influence on response to vascular disrupting agents (VDAs). Alternative splicing of the VEGF-A gene influences tumour vascular maturation and impacts on vascular disrupting therapy; specifically VEGF188/9 is involved in recruitment of pericytes to tumour blood vessels, which in turn confers resistance to the effects of the tubulin-binding VDA, combretastatin A-4-P (CA-4-P). One aim of the current research is to determine the mechanisms by which VEGF188/9 influences vascular maturation, including pericyte recruitment and integrity of endothelial-endothelial and endothelial-pericyte adherens junctions. Activation of Rho-GTPase signalling pathways has been found to account for much of the CA-4-P-induced re-modelling of the actin cytoskeleton of endothelial cells in vitro and contributes to tumour necrosis induction in vivo. In addition, deciphering the cell signalling pathways associated with the different VEGF isoforms and how they interact with CA-4-P effects will provide mechanistic information on resistance mechanisms to tubulin-binding VDAs.
This programme of work is funded by Cancer Research UK and EPSRC, with additional funding from MRC and the Department of Health and is carried out jointly with Professor Martyn Paley, Department of Human Metabolism, as co-PI. The aim is to develop imaging bio-markers for evaluating VDAs and other vascular-targeted therapeutics in clinical trials. This programme focuses on developing magnetic resonance imaging (MRI) techniques, including magnetic resonance spectroscopy imaging (MRSI), as well as mass spectrometry imaging of tissue sections. Hyperpolarisation techniques, both for 129Xe gas and dynamic nuclear polariation (DNP) for 13C are being used to enhance signal intensity. Blood flow rate and oxygenation are the efficacy end-points of primary interest. For blood flow, the utility of 129Xe uptake into tissues, following inhalation of the hyperpolarised gas, is being evaluated. For oxygenation, the kinetics of metabolism of injected hyperpolarised 13C-pyruvate to 13C-lactate, as well as the decay of signal from 129Xe, which is oxygen dependent, are being investigated. A range of techniques, including optical imaging, are being used to validate results from MRI/MRSI experiments. Mass spectrometry imaging (in collaboration with Professor Malcolm Clench, Sheffield Hallam University) is being used to evaluate the response of tumours to VDAs, with the aim of identifying novel markers of both efficacy and resistance. Nano-particle technology is being employed to investigate the maturation status of tumour blood vessels, which is known to strongly influence tumour response to VDAs, making it a potentially useful marker for selecting patients most likely to benefit from this type of treatment. These techniques are being developed in pre-clincal models of cancer, with the aim of translating them to clinical studies.
- Other Projects
A BBSRC CASE PhD studentship funds work with AstraZeneca to investigate the effects of growth factors and vascular-targeting agents on blood vessel development and function using optical imaging. We are also working with Professor Claire Lewis on the role of tumour-associated macrophages in the response of tumours to VDAs. Part of this work employs a novel zebrafish model of cancer in which macrophages express mCherry and hypoxic cells express GFP. Using optical imaging, this powerful genetic model will be used to determine the role of hypoxic macrophages in tumour development and response to treatment.
See link on the right