Centre for Molecular & Cellular Biology – 1994
1994 – $1.096 million research grant
Research Institution: Centre for Molecular & Cellular Biology, University of Queensland, Brisbane, Queensland
Director of Research: Professor John Mattick
Cancer type/research focus: skin cancers, cancer of the kidney, leukaemia and various childhood cancers
Further Details / Outcomes:
Director, Professor John Mattick – Update for 2002
The Institute for Molecular Bioscience, University of Queensland has continued to play an active role in cancer research. Dr Wicking and Prof Wainwright have demonstrated a link between levels of cholesterol production within the cell and the function of the ‘patched’ gene product. They had previously demonstrated that mutations in the ‘patched’ gene leads to skin cancer. Dr Sturm has shown that expression of the â3 integrin gene in melanoma leads to the production of an anti-adhesive protein, osteonectin, which is likely to facilitate the spreading of melanoma. Professors Koopman and Muscat have identified a novel gene regulating the formation of new blood vessels called Sox18. As the formation of new blood vessels is critical for tumour progression, they are investigating the therapeutic value of Sox18 blockade. Associate Professor Little has used microarray chips to identify the gene products which are regulated by the WT1 gene to prevent the formation of the childhood renal cancer, Wilms’ tumour. Professor Waters has shown that a novel regulator of cytokines, CIS, is a marker for breast cancer. The Institute for Molecular Bioscience is soon to relocate to the Queensland Bioscience Precinct. This building complex will house state-of-the-art facilities enabling IMB to undertake world-class research to better understand human biology. Former occupants of the ACRF laboratories will continue their cancer research in this new complex.
Hedgehogs and skin cancer
CA Wicking and BJ Wainwright
The hedgehog signalling cascade plays a pivotal role in the formation of a number of tumour types, most notably basal cell carcinomas of the skin. To fully understand the mechanisms of tumourigenesis in hedgehog-related cancers we need to understand the processes regulating this signalling cascade. The team is focusing on those regulatory mechanisms which act to ensure that the hedgehog signal is correctly transmitted from the cell surface. They have adopted a cell biological approach to investigate these processes at the cellular level. There are a number of key molecules involved in reception of the hedgehog signal including patched and smoothened. They have determined the localisation of patched within the cell both at the light and electron microscopic level. They are now involved in determining those cues involved in trafficking these key molecules around the cell. One factor that seems to play a role in these trafficking events is the level of intracellular cholesterol, and the team is investigating the effect of altered cholesterol levels on hedgehog signalling and patched and smoothened localisation. It seems clear that cholesterol levels and intracellular trafficking events play a major role in regulation of hedgehog signalling and they are involved in dissecting these mechanisms at the cellular level.
The role of integrins in metastatic melanoma
RA Sturm
Expression of the â3 integrin gene in melanoma in situ has been found to be the single most important marker of metastasis and long term patient survival yet discovered. Dr. Sturm has been conducting experiments to investigate the effects of this expression using Adenoviral gene transduction of the â3 integrin subunit into radial growth phase (RGP) melanoma cell lines to perform differential gene screening. A skin reconstruction model has been used to assay the invasiveness of RGP melanoma cells after ectopic â3 integrin expression and these studies have discovered induction of the anti-adhesive protein osteonectin is required for metastasis to take place.
Sox transcription factors and the molecular control of tumour angiogenesis
PA Koopman and GEO Muscat
The team discovered a gene, Sox18, that is critical for development of blood vessels. Since SOX genes have been implicated in many forms of cancer, and given the essential role of angiogenesis in tumour progression, they are studying the expression of Sox18 and closely related genes in various types of human tumours. The team is examining the rate of tumour progression in mice mutant for Sox18. In addition, they are conducting pilot studies to test the idea that therapeutic blocking of the function of Sox18 will suppress the development of a blood supply to tumours, and so prevent tumours from growing and spreading.
The Wilms’ tumour suppressor protein regulates cell morphology, proliferation and motility.
The Wilms’ tumour suppressor gene, WT1, was identified as a gene that was inactivated in the childhood cancer of the kidney, Wilms’ tumour. WT1 is also mutated in some tumours of the gonad and some forms of acute leukaemia in children. WT1 proteins are found within the nucleus of the cell and their structure suggested that they acted by binding to the DNA regulatory elements controlling the expression of other genes. Wilms’ tumour is the most common solid tumour in children. While the loss of activity of WT1 is enough to cause the formation of a Wilm’s tumour, the team has shown that only 10% of Wilms’ tumours carry mutations in this gene. It is therefore likely that some of the genes regulated by WT1 are mutated in these other tumours. However, the real targets of WT1 have not been identified. The team has been investigating the overall changes in levels of gene expression in cell lines where the WT1 protein is either turned on over time, or repressed over time. For this they have used glass microchips containing 15-20,000 genes. In this way they have found a number of critical enzymatic pathways which are affected by WT1. They have also shown that WT1 does not only work by binding to DNA but can also directly bind to the RNA expressed from certain genes. The team has identified a group of RNAs that WT1 interacts with directly and these again indicate the way in which is regulating cell proliferation, migration and hence tumour formation.
The CIS gene and breast cancer
MJ Waters
Cytokines are important factor in breast cancer survival and transformation. They are regulated by a recently discovered family of proteins, Suppressors of Cytokine Signalling (SOCS). In a survey of breast tumours by in situ hybridisation, the team found elevation of transcripts for members of the SOCS family. This was confirmed by immunohistochemistry. Examination of 10 breast cancer lines showed that CIS was elevated in every line (compared to the two breast cell lines), both as transcript (by Northern) and by immunoblot. They then showed that CIS is able to activate the important mitogenic kinase, MAP kinase, through use of a reporter assay in CIS transfected cells. The team is currently evaluating the effect of CIS overexpression on proliferation and morphology of a breast cell line.
Growth hormone, cell proliferation and cancer
MJ Waters
Growth hormone acts on essentially all cells in the body to regulate hypertrophy, hyperplasia and phenotype. The team has shown growth hormone receptors to be present in the nuclei of many cell types, notably in cancers. To investigate this, they have introduced a nuclear localization signal on to the amino terminus of the GH receptor, and stably transfected cell lines with this construct. In their model of cell proliferation (pro-B line BaF/B03), nuclear GHR results in factor-independent proliferation in 5% serum (but not in wt GHR expressing cells). The team has subsequently used chromatin immunoprecipitation assays to identify a gene promoter that binds directly to the GH receptor, and shown the transcript is elevated by GH. They have also identified important coactivators which bind directly to the extracellular domain of the GH receptor, which, when stably co-expressed in BaF populations, increase the maximum proliferative response to GH. The team will now examine if NLS-GHR expressing BaF/B03 lines are tumorigenic in nude mice.
New building for the Institute for Molecular Bioscience
The Institute for Molecular Bioscience, along with aspects of CSIRO Livestock Industries, Plant Industry and Sustainable Ecosystems will relocate to the Queensland Bioscience Precinct in early 2003. This building complex will house state-of-the-art facilities enabling IMB and CSIRO to undertake world-class research to better understand human and animal biology. With around 800 scientists and support staff the QBP is a national leader in bioscience research and application making important contributions to the Queensland and Australian economies. Former occupants of the ACRF laboratories will continue their cancer research in this new complex.
