Cancer is a complex multifactorial genetic disease for which only a limited number of genes involved have been identified.  It is now clear that increased insulin/IGF signalling (IIS) plays a major role in driving excess growth associated with at least 50% of human tumours.  In addition, it is already well established that cells become more resistant to the action of the hormone insulin in the most common form of diabetes, Type II diabetes.  By improving our understanding of how cells respond to insulin/IGFs at the genetic level, we hope to impact on the treatment of both of these major human diseases.

Current Research Programme

We and other groups are teasing apart the IIS pathway using the powerful genetic approaches offered by the fruit fly, Drosophila melanogaster.  These studies have revealed that both endocrine and local inputs from circulating nutrients regulate insulin-mediated growth.   

We have focused on understanding how a cell’s response to local nutrients modulates the effects of insulin.  The genetics of the fly have helped us to identify a previously unsuspected class of membrane-bound molecules, the proton-assisted amino acid transporters or PATs, as being potent local modulators of IIS within non-endocrine tissues.  These studies have revealed that the effects of PATs are dramatically increased by IIS and that some of the PATs can also function at very low amino acid levels, which may be particularly relevant to growth regulation in tumour cells.

Since the PATs can be found at the cell surface, they may make particularly attractive targets to correct problems in IIS associated with the diseased state using drugs or even through dietary changes.  Our lab is therefore studying the mechanisms by which PATs control growth.  In addition, we are particularly interested in elucidating the mechanism by which the PATs are regulated as this may provide a significant new route to treating cancer and diabetes. 

Genetic analysis in the fly has allowed us to rapidly identify a number of candidate genes affecting PAT activity and we are currently looking at whether they interact with the PATs to regulate IIS.  We hope that this work will broaden our understanding of how cells respond to local nutrient levels and how this impacts on the range of physiologically important insulin-linked processes required for normal development and homeostasis, which go awry in the diseased state.

Deborah Goberdhan