Dr Toby Phesse

Dr Toby Phesse

Research Fellow

School of Biosciences

Email:
phesset@cardiff.ac.uk
Location:
Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ

Dr Phesse was awarded his PhD from the University of Warwick where he studied the co-operation between Wnt signalling and TGF-β signalling during embryonic development.  It was during this project that he learned of the important role that Wnt signalling played during cancer, and subsequently secured a post-doc position in the laboratory of Professor Alan Clarke at Cardiff University. It was in Alan’s lab that he cultivated his primary research interest, studying how cell signalling regulates homeostasis, stem cell function, regeneration and cancer.  His work has focussed mainly on the Wnt signalling pathway and the gastrointestinal tract, although he has also investigated other organs including the liver, prostate and skin, with the underlying goal of identifying novel therapeutic strategies for the treatment of disease, and especially cancer.

After three successful years with Alan, Toby obtained a Fellowship from the British Council to work at the Ludwig Institute in Melbourne to study the interaction between Wnt signalling and gp130/Stat3 signalling in GI cancer. He published this work in Cancer Cell in 2009 which has since been cited over 300 times. He subsequently maintained continuous National Health Medical Research Council funding for the following 6 years which enabled him to manage a small research group in a variety of institutes, including the prestigious Walter and Eliza Hall Institute and the University of Melbourne, studying the role of cell signalling in regeneration and cancer.

In 2016 he was appointed Senior Research Fellow and co-lab head at the University of Melbourne, before being awarded additional UK based fellowships (Wellcome Trust and Capital Medical University) to facilitate his move back the Cardiff as a Fellow at the new established European Cancer Stem Cell Research Institute at Cardiff University.

My primary research interest is in understanding how cell signalling controls homeostasis, regeneration, stem cell function and disease, with a focus on Wnt signalling in the gastrointestinal tract. Many of the cell signalling pathways that are critical for embryonic development, homeostasis and regeneration of epithelial tissues are deregulated during disease, and in particular cancer. Thus, by understanding the molecular events that regulate cell signalling during these biological processes, and the aberrations that result in deregulation and disease, we aim to identify novel therapeutic strategies.

My lab uses a combination of advanced in vitro techniques, such as organoid cultures (Fig. 1), together with sophisticated mouse models (Fig. 2), to gain new insights into the requirement for cell signalling during the biology of the adult gastrointestinal epithelium, and thus understand how deregulated signalling results in disease.

Stem cells are intimately associated with cancer, as they have frequently been demonstrated to be the cell of origin for several different cancers including the intestine. The discovery of Lgr5 as a marker of intestinal stem cells has provided a powerful research tool to enable further insight into the biology of the intestine and the role of stem cells in cancer.  Indeed, Lgr5 also marks a population of cancer stem cells which is able to provide the proliferative and self-renewal properties of intestinal tumours. Thus, understanding what regulates stem cells is a major interest in the field and our lab is particularly interested in the role of Wnt signalling.

Although the Wnt pathway is deregulated in around 85% of colon tumours it is also required, at lower levels, for the normal homeostatic function of the intestine, and during regeneration. The cytoplasmic signal transducers involved in Wnt signalling have been well characterised, and current research continues to gain new insights into its complexity and interaction with other pathways (Bollrath and Phesse et al, Cancer Cell, 2009 and Phesse et al, Science Signalling, 2014). Compared to the cytoplasmic Wnt regulators, the Wnt receptor complex is relatively poorly understood.  Indeed, it is still not fully documented which of the 10 mammalian Frizzled Wnt receptors bind to which of the 19 mammalian Wnt ligands. It was only in 2015 that we demonstrated that Frizzled7 is the predominant Wnt receptor required for intestinal stem cell function (Flanagan and Phesse et al, Stem Cell Reports, 2015 and reviewed in Phesse et al, Cancers, 2016), and current projects are investigating the role of this receptor in other organs and disease settings.

The bacteria Helicobacter pylori is estimated to infect around 50% of the world’s population, and is strongly associated with the development of gastric cancer, but very little is known regarding how infection triggers this pathology.  In collaboration with colleagues at the Capital Medical University in Beijing, we are also investigating the requirement for Wnt signalling in H pylori associated gastric cancer.

Key Collaborators

Professor Owen Sansom – Beatson CRUK, Scotland

Professor Elizabeth Vincan – University of Melbourne, Australia

Professor Nick Barker – AStar Institute, Singapore

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