Glyco-oncology
Led by Professor John Gallagher
Proteoglycans, with their long sulphated glycosaminoglycan (GAG) chains, are common constituents of the surface and surrounding matrix of mammalian cells (Figure 1). The most complex GAG is heparan sulphate (HS), which is mainly found associated with two families of plasma membrane proteins, the transmembrane syndecans and the GPI-anchored glypicans. HS is a 'lower affinity' co-receptor for many growth factors (such as the FGFs, HGF/SF and VEGF165) and morphogens (eg Wnt/Wg and hedgehog proteins), and binding to HS is a prerequisite for subsequent productive interactions with their high-affinity signaling receptors.
In parallel, HS also interacts with various matrix proteins, such as fibronectin, and plays a crucial role in cell-matrix adhesion. It is not surprising that one consequence of the wide usage of HS as a co-receptor in cell growth, adhesion and migration is that it is essential for normal embryonic development and for regulated post-natal growth. Moreover, several of the growth factors (or their receptors) that utilize the HS co-receptor are mis-expressed, over-expressed or mutated in human cancer, suggesting that the HS-growth factor interaction is a suitable target in cancer therapy.
The group's research has three major objectives:
- To determine structure-function relationships in HS
- To elucidate the role of HS in the self-renewal and differentiation of embryonal stem cells
- To identify HS sequences that antagonize growth factor signaling and may be useful in drug design
Translational research
One of the more intriguing findings from our studies on HS-FGF interactions is that the GAG chain contains inhibitory as well as activating sequences, and this has raised our interest in the chemical design of FGF antagonists. This work has been spearheaded by Professor Gordon Jayson (glycoangiogenesis group) who works in close collaboration with us, and with Dr John Gardiner in the Chemistry Department of the University. Significant advances have been made in the organic synthesis of potential FGF antagonists for testing and optimization through FGF-mediated in vitro and in vivo angiogenesis assays. In parallel, we are also collaborating with Dr Jim Wilkinson and Dr Sylvie Ducki (Centre for Molecular Drug Design, Salford University) in the synthesis and screening of novel GAG mimetic structures for the potential to antagonize HGF/SF and/or FGF activities.
Staff members
| Name | Job title | Email address |
|---|---|---|
| John Gallagher | Professor of Medical Oncology | jgallagher@picr.man.ac.uk |
| Malcolm Lyon | Senior Research Fellow | mlyon@picr.man.ac.uk |
| Claire Johnson | Postdoctoral Research Associate | cjohnson@picr.man.ac.uk |
| Christopher Robinson | Postdoctoral Research Associate | christopher.robinson@manchester.ac.uk |
| Jonathan Deakin | Senior Scientific Officer | jonathan.deakin@manchester.ac.uk |
| Nijole Gasiunas | Senior Scientific Officer | nijole.gasiunas@manchester.ac.uk |
| Mary Coyle | Research Technician | mary.coyle@manchester.ac.uk |
References
- Merry, C.L.R. et al. (1999) J. Biol. Chem. 274, 18455-18462
- Murphy, K.J. et al. (2004) J. Biol. Chem. 279, 27239-27245
- Lyon, M. et al. (2004) J. Biol. Chem. 279, 43560-43567
- Robinson, C.J. et al. (2005) J. Biol. Chem. 280, 42274-42282
- Robinson, C.J. et al. (2006) J. Biol. Chem. 281, 1731-1740
- Lyon, M. et al. (2002) J. Biol. Chem. 277, 1040-1046