Cell Cycle & Cancer Genetics Achievements, Awards & Prizes

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Cell Cycle & Cancer Genetics Achievements, Awards & Prizes - Research at Peter Mac

Awards & Prizes

Dr Patrick Humbert

National Health and Medical Research Council (NHMRC) RD Wright Career Development Fellowship, 2005–09. NHMRC Biomedical Career Development Fellowship, Level 2, 2009-12.

Suzie Roczo

Department of Pathology Deans Prize, The University Of Melbourne, Top Honours Student Pathology in 2008.

Recent Invited Presentations

Dr Patrick Humbert

RIKEN Centre for Developmental Biology Symposia, Kobe, Japan, March 2009. Cell Press Symposium, San Francisco, USA, March 2009. COMBIO 2009, Christchurch, New Zealand, December 2009. 10th National Prostate Cancer Symposium, Melbourne, Vic, August 2009.

Imogen Elsum

Gordon Research Conference, Waterville Valley, USA, June 2009.

Lorey Smith

Australasian Microarray Associated Technologies Association Conference, Katoomba, NSW, October 2009.

Recent Research Achievements

DEMONSTRATION THAT A LARGE GENETIC NETWORK COOPERATES WITH H-RAS TO PROMOTE CELL INVASION AND TRANSFORMATION THROUGH DEREGULATION OF MAPK SIGNALLING. Scribble is a core polarity regulator first identified in Drosophila and shown to have important roles in the regulation of tissue architecture and cell proliferation. In addition, Scribble loss cooperates with activated oncogenes Ras or Notch to give rise to invasive and metastatic tumours in Drosophila. Our laboratory has recently shown that loss of the mammalian homologue of Scribble can similarly cooperate with activated H-Ras to drive invasion of mammary epithelial cells in 3D organotypic culture. Conversely, we also observe suppression of Ras-mediated cell transformation phenotypes through ectopic expression of Scribble, including loss of polarity, invasion in 3D culture and importantly, anchorage independent growth. How Scribble regulates oncogenic Ras signaling is currently unknown. We have conducted an unbiased large-scale, functional genomics screen to identify the genetic requirements for Scribble to suppress Ras-driven cell transformation, combining RNAi technology with Next Generation Sequencing. We have screened ~20,000 shRNA constructs from the Open Biosystems human genome-wide miR30-based lentiviral shRNA library, utilizing the well defined soft agar anchorage independent colony assay. Through this approach, we have identified 141 candidate genes that were significantly enriched in our selected sample sets, identifying them as important regulators and effectors of Scribbles tumour suppressive functions in mammalian systems. We have subsequently performed both primary and secondary validation experiments for a number of key targets, confirming not only their requirement for the inhibition of Ras-driven oncogenesis, by Scribble but also their ability to cooperate with oncogenic Ras to drive invasive phenotypes in vitro. GPSM2 (LGN/PINS) has emerged from these studies as a key candidate, and we provide evidence of its role in the regulation of tumourigenesis in vivo in mice, and further show strong correlations between its de-regulation and the progression of human breast cancer. DEMONSTRATION THAT LOSS OF HUMAN SCRIBBLE COOPERATES WITH H-RAS TO PROMOTE CELL INVASION THROUGH DEREGULATION OF MAPK SIGNALLING. Activating mutations in genes of the Ras-MAPK pathway occur in approximately 30% of all human cancers. However, mutation of Ras alone is rarely sufficient to induce tumour development. Scribble is a polarity regulator recently isolated from a Drosophila screen for events that cooperate with Ras mutation to promote tumour progression and cell invasion. In mammals, Scribble regulates directed cell migration and wound healing in vivo, but no role has been identified for mammalian Scribble in oncogenic transformation. We have now shown that in human epithelial cells expressing oncogenic Ras or Raf, loss of Scribble promotes invasion of cells through extracellular matrix in an organotypic culture system. Further, the mechanism by which this occurs is through the regulation of MAPK signalling by Scribble. The suppression of MAPK signalling is a highly conserved function of Scribble as it also prevents Raf-mediated defects in Drosophila wing development. Our data have identified Scribble as an important mediator of MAPK signalling and provide a molecular basis for the observation that Scribble expression is decreased in many invasive human cancers. [Reference: Dow LE et al., (2008) Oncogene 26:2272–82.]