Cell Cycle and Development

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Cell Cycle and Development - Research at Peter Mac

We use the model organism, the vinegar fly Drosophila, to investigate the action of the junctional neoplastic tumour suppressors and ECM proteins in tumourigenesis, how these cooperate with oncogenes in tumourigenesis and to identify small molecule inhibitors of tumour growth in vivo.

Research focus

Modelling cancer in Drosophila. Mechanism of action of junctional neoplastic tumour suppressor genes, lgl/scrib/dlg. Role of the extracellular matrix protein Sparc in tumourigenesis. Screening for anti-cancer drugs using Drosophila cancer models.

Research overview

The Cell Cycle and Development laboratory uses the genetically amenable model, the vinegar fly Drosophila, to study mechanisms controlling cell proliferation and tumourigenesis within the context of a whole animal. Our major focus is on the neoplastic tumour suppressors scrib, dlg and lgl, which affect cell polarity, proliferation and migration. We have shown that lgl mutant clones show upregulation of the key cell cycle gene, cyclin E, and ectopic cell proliferation, independent of cell polarity defects, showing that lgl directly affects proliferation independent of cell architectural defects. To identify the pathways misregulated in scrib/dlg/lgl mutants, we have carried out genetic screens and microarray expression profiling, which has revealed that several signalling pathways are misregulated. Despite the ectopic cell proliferation that occurs in scrib/dlg/lgl mutant clones, the mutant tissue does not overgrow due to cell death or differentiation. We have developed a two-hit cancer model in flies, where co-expression of oncogenic Ras or Notch in scrib/dlg/lgl mutant clones overcomes the restraining forces of cell death and differentiation to result in the generation of invasive tumours. By genetic screens we have identified other genes that can cooperate with scrib mutants or with oncogenic Ras in tumourigenesis and are analyzing their mechanism of action. In addition, we are using our Drosophila cancer models to screen for small molecule inhibitors that specifically target the tumours. Through collaboration with Drs Patrick Humbert and Sarah Russell we are translating this work into mammalian epithelial or T cells and mouse models. We are also investigating the role of extracellular matrix proteins, in particular Sparc, in tumourigenesis in collaboration with Professor David Bowtell (Cancer Genetics and Genomics laboratory).