Dr. Ian Chin-Sang Department of Biology, Queen's University Using a tiny worm to help solve a big problem like cancer
Cancer often results when normal signal transduction pathways go awry due to the abnormal regulation or function of the genes in these pathways. A major oncogenic pathway is the Insulin and Insulin Growth Factor Signaling (IIS) pathway. The insulin and insulin-like growth factor signaling (IIS) pathways have multiple functions in development, metabolism, reproduction, lifespan and behaviour. A very important negative regulator of this pathway is the tumour suppressor PTEN. In a remarkable parallel, loss of the C. elegans PTEN orthologue (DAF-18) causes cells to divide when they should remain quiescent. Furthermore, the human PTEN can functionally replace worm DAF-18. When C. elegans hatch in the absence of food it shuts down its development until food is available in a process called L1 arrest. Normally during L1 arrest the Q neuroblasts remain quiescent, however, in daf-18 mutants the Q neuroblasts proliferate, migrate and differentiate. We have used genetic suppressor screens and pharmacological tests to identify novel branches and regulators of the C. elegans IIS. We also systematically overexpressed each of the 40 Insulin-like peptides in C. elegans to provide roles for each. We showed that some insulin peptides can activate the receptor while some inhibit the receptor, while others have mixed function (agonists or antagonists) depending on the developmental process. We have used this data to determine what makes an insulin-like peptide an activator or inhibitor of the DAF-2 insulin-like receptor. Our research using C. elegans has identified novel regulators of IIS and will help in the clinical setting by providing valuable information on human PTEN variants of unknown significance. The inhibitory insulin-like peptides will provide mechanistic insight for therapies to treat hyperinsulinemia related diseases.