The Quinn Lab - Drosophila models for cancer
 |
 |
 |
Principle Investigator |
Research Assistant |
Research Assistant Ms Nicola Cranna |
Research Background
Aberrant proliferation leads to cancer
Our research involves developing animal models to understand the initiation and progression of cancer. We focus on genes, called oncogenes and tumour suppressor genes, which are required for tight regulation of the cell division cycle. The movement of cells through the cell cycle must be carefully monitored to ensure inappropriate proliferation does not result in tissue overgrowth, genomic instability and ultimately cancer initiation.
Our lab determines how cell cycles are regulated by developmental signals in the whole animal using the excellent genetic model system Drosophila melanogaster, which has been studied for over 90 years to understand complex in vivo interactions. Developmentally regulated cell proliferation has been well characterised in the fly, with cell cycles from embryonic, larval and adult tissues being well defined.
Importantly for our studies the main elements of the cell cycle machinery have been conserved through evolution from Drosophila to mammals. This means that knowledge derived from our Drosophila studies can be applied to the complex pathways that coordinate proliferation in mammals, which are linked to cancer progression in humans. The current understanding of the genetics of human cancer has therefore been greatly aided by studies using flies as an animal model.
 |
 |
Drosophila models for regulation of the Myc oncogene
Deregulated c-myc expression occurs in most human cancers, but despite this our understanding of the developmental signals regulating c-myc expression is incomplete. Drosophila Myc, dMyc, is functionally homologous to the c-myc proto-oncogene, which is universally important for growth and cell cycle progression. In mammals, multiple signals control c-Myc and studies in Drosophila suggest dMyc is regulated by interplay between developmental signals. Our research aims to use Drosophila models to identify factors important for dmyc regulation, cell growth and cell cycle progression including: 1) the complex array of developmental and growth signals upstream of dMyc; and 2) mechanisms for control of dmyc transcription. To facilitate this work we have use two Drosophila models for monitoring dmyc transcription and cell growth 1) the wing imaginal disc and 2) the gonads, which we use to model regulation of dmyc in stem cells.
FIR/Hfp is an essential myc repressor
We previously demonstrated that Half Pint (FIR/Hfp) behaves as a tumour suppressor gene. FIR/Hfp is an essential dmyc transcriptional repressor, which is regulated by Wg (Wg, Wnt family morphogen) signalling (Quinn et al, Development 2004). Thus we believe FIR/Hfp provides a connection between developmental signals and dmyc repression. In humans, FIR mutations have been linked with colorectal cancer, but the developmental signals impacting on FIR are currently unknown.
The Drosophila wing imaginal disc has provided an excellent model for the study of developmental signals regulating growth and cell cycle. We have characterised a dmyc-lacZ enhancer trap line, which replicates the mRNA expression pattern for dmyc in the larval wing (Fig. 1 A,B). Using this model system we have demonstrated that FIR/hfp is essential for repression of dmyc transcription in vivo as FIR/Hfp RNAi results in increased dmyc promoteractivity (Fig. 1 C,D). As part of our current research we use this model to determine the interplay between upstream growth signals and other factors required for FIR/Hfp-dependent dmyc repression.
Fig. 1 - FIR/Hfp loss-of function drives increased dmyc transcription and cell growth.
(A,B) Control clones. (C,D) FIR/Hfp RNAi clones, marked with GFP.