Professor John Ladbury

The Ladbury Group work primarily on intracellular signal transduction mediated by plasma membrane-localised receptor tyrosine kinases (RTKs). Canonical RTK signalling is based on up-regulation of kinase activity and the subsequent provision of phosphorylated tyrosine residue-containing binding sites for recruitment of downstream signalling proteins. The Ladbury Group have discovered that RTKs are also capable sustaining recruitment of downstream effector proteins via interactions with proline-rich sequences and downstream proteins with SH3 domains. Since the majority of RTKs have proline-rich sequences in their C-termini, the opportunity for non-canonical signalling appears to offer a new frontier in RTK activity. Although it is hypothesised that this Tier 2 signalling (Tier 1 being the canonical kinase-driven signalling) is likely to be responsible for cellular homeostasis and 'house-keeping' functions, when aberrant it can lead to cancer and metastatic outcomes. In addition, Tier 2 signal transduction could provide a mechanism for observed resistance to RTK-targeted inhibition.

The Ladbury Group are developing spheroid/organoid systems and platform technologies to investigate Tier 2 signalling in progression from Barrett's Syndrome to adenocarcinoma in oesophageal cancer, as well as in resistance mechanisms in glioblastoma. The ability to investigate patient-derived organoids in devices capable of modulating microenvironmental changes provides an opportunity to explore the molecular mechanisms associated with cell survival and cancer progression under conditions that closely recapitulate those experienced physiologically.