Tumour Growth Control Group (CRUK) - Sir William Dunn School of Pathology
We are investigating molecular and functional aspects of tumour growth, and how the molecules that control growth can be targeted for application to human cancer therapy.
Focus on the M6P/IGF2 Receptor
Our initial focus has been on the molecular and genetic interactions of ligands of the Mannose 6-phosphate/ Insulin-like growth factor 2 receptor (IGF2R). The gene expressing the ligand IGF2 (Igf2) is reciprocally imprinted with respect to the gene expressing the IGF2 receptor (Igf2r), a receptor that functions to sequester and inhibit IGF2 and mannose 6-phosphate ligand function. The receptor regulates embryonic growth and is mutated in cancers. We have performed detailed structural studies with close collaborating groups of Yvonne Jones (STRUBI, Oxford) and Matt Crump (CRUK Co-Investigator, Chemistry, Bristol). These have lead to a basic understanding of ligand- receptor interactions that have lead to further structure and function experiments. Moreover, structural and functional studies have lead to the development of a novel ligand trap for IGF2, the tumour growth promoting ligand. A functional genetic approach in murine models has detailed function of Igf2 and Igf2r during development and tumourogenesis that have provided insights into the mechanisms of control of tumour growth. In particular, we have studied Igf2 interactions with loss of tumour suppressor gene function (Apc, Pten, Cdh1 and p53). This information provides an excellent basis to study how tumour progression is orchestrated in vivo from developmental origins, pre-malignant tissues to established tumours. Finally, we are now applying this knowledge to mesenchymal derived tumours in human, particularly in bone sarcoma.