Oncology Research Unit (Cancer Research)

Cellular Oncology Group

• Research Directions
• Group Leader Profile
• Student Projects
• Grants
• Recent Publications

Research Directions

The structure of all cells underpins their function. In the case of cancer, profound changes in cell structure accompany the induction and progression of malignancy. The cellular oncology group is establishing the primary mechanisms by which the actin cytoskeleton regulates cell structure and function. We use a variety of cellular systems to identify principles of actin filament organisation and how this translates into specific cell shapes and internal structures. The projects utilise genetic manipulation of components of the actin filament (actin and tropomyosin) both in cell culture and in mouse models.

The lab aims to:

• Identify the role of specific actins and tropomyosins in regulating cell structure in normal and malignant cells.
• Establish the relationship between specific organisation of the actin cytoskeleton and cell function.
• Develop cell structure analysis as a diagnostic for different tumour types.

Group Leader Profile - Professor Peter Gunning

Professor Peter Gunning (PhD) is the Group Leader of the Cellular Oncology Group of the Oncology Research Unit at The Children's Hospital at Westmead (CHW). Prof Gunning held the position of Head of the Oncology Research Unit from it's initiation in mid-1997 to March 2008. He was also Chair, CHW Research Division from 1998-2007. He is a National Health and Medical Research Council (NHMRC) Principal Research Fellow. Prof Gunning has also served for a period of 5 years as the ASMR representative on the Board of the NSW Cancer Council, and for 3 years chaired their Research Committee.

Professor Gunning spent both his undergraduate and postgraduate years studying biochemistry at Monash University, Melbourne. Postdoctoral Fellowships (1977-1982) and Senior Research Associate positions (1982-1987) at Stanford University, USA followed this. He then spent 10 years as a Senior Research Fellow at the Children's Medical Research Institute, heading the Cell Biology Group, before taking up the position as Head of the Oncology Research Unit (1997-2008). Peter was appointed to his Professorship through the University of Sydney in 1997.

The primary focus of Prof Gunning's research group, cellular oncology group, is the regulation of cell and tissue architecture and its modification during tumourigenesis. Prof Gunning, and the laboratory, have made a significant and internationally recognised contribution towards understanding the relationship between disruption of the actin cytoskeleton and cancer. This includes the first demonstration that a mutation in the actin cytoskeleton can induce tumour formation by human cells.

During the last 5 years Prof Gunning has tackled a new initiative, the use of both conventional transgenic and gene knock-out approaches to disrupt cell most important novel finding from these animals is that altered composition in the brain leads to neuro-degeneration and in skeletal muscle to a muscular dystrophy. These results indicate that actin filament isoforms may directly contribute to more diseases than is currently recognised in humans.

Prof Gunning has over 130 original scientific publications including invited reviews for BioEssays, Annual Review of Cell and Developmental Biology, Nature Publishing Group's Encyclopedia of the Human Genome, Trends in Cell Biology and Current Cancer Drug Targets.

Prof Gunning's scientific contribution is not confined to the area of overlap between cancer and the cytoskeleton, as evidenced by (cancer focused) invited presentations, Scientific Discipline involvement, Editorial Board membership and commercialisation activities, as described below.

• Annual Scientific Conference of the Australian and New Zealand Children's Cancer Study Group (ANZCCSG), May 2001:Molecular Diagnostics and Childhood Cancer.
• Annual Scientific Conference of the ANZCCSG, June 2003: Plenary: Bioethics Symposium: The Molecular Revolution: Opportunities And Dilemmas. Convener and Chairman.
• Annual Scientific Conference of the ANZCCSG, June 2003, Plenary: Preparing for the Molecular Revolution. Convener and Chairman.
• Member, National Cancer Grant Committee (2000).
• Reviewing of grants for NHMRC, NZMRC, National Cancer Grant Assessment Panel.
• Member: ANZCCSG, Paediatric Oncology Group, USA (POG).
• Editorial Board Membership: Recent Patent Reviews on Anti-Cancer Drug Discovery (Bentham Science).
• Commercialisation: Chair, Westmead Research Hub Intellectual Property and Commercialisation Committee (2000 - 2007).
• Founding Chair, BioLink Partners Ltd, 2004 - 2007.

Grants

NHMRC Fellowship 358707 (Gunning P)
2005-2009: $125,250 p.a.

NHMRC Project Grant 352491 (Gunning P and Schevzov G)
Molecular Genetics of Cell and Tissue Structure.
2005-2009: $205,375 p.a.

NHMRC Project Grant 321705 (Gunning P, Hardeman E, Kee A)
A novel cytoskeletal structure in muscle is associated with Muscular Dystrophy.
2005-2007: $122,000 p.a.

NHMRC Project Grant 321701 (Hardeman E. North K, Gunning P)
Novel features and mechanisms of congenital myopathies.
2005-2007: $159,250; $149,250; $149,250

NHMRC Enabling Grant - Special Facilities 402784 (Elliott E, Bower C, Kaldor J, et al.)
Australian Paediatric Surveillance Unit: A collaborative network for child health research.
2006-2010: $200,000 p.a.

Recent Publications

Domazetovska,A., Ilkovski,B., Cooper,S.T., Ghoddusi,M., Hardeman,E.C., Minamide,L.S., Gunning,P.W., Bamburg,J.R., and North,K.N. (2007). Mechanisms underlying intranuclear rod formation. Brain 130, 3275-3284.

Macarthur,D.G., Seto,J.T., Raftery,J.M., Quinlan,K.G., Huttley,G.A., Hook,J.W., Lemckert,F.A., Kee,A.J., Edwards,M.R., Berman,Y., Hardeman,E.C., Gunning,P.W., Easteal,S., Yang,N., and North,K.N. (2007). Loss of ACTN3 gene function alters mouse muscle metabolism and shows evidence of positive selection in humans. Nat.Genet. 39, 1261-1265.

Palmer,S.J., Tay,E.S., Santucci,N., Cuc Bach,T.T., Hook,J., Lemckert,F.A., Jamieson,R.V., Gunning,P.W., and Hardeman,E.C. (2007). Expression of Gtf2ird1, the Williams syndrome-associated gene, during mouse development. Gene Expr.Patterns. 7, 396-404.

Chang,A.C., Hook,J., Lemckert,F.A., McDonald,M.M, Nguyen,M.A., Hardeman,E.C., Little,D.G., Gunning,P.W., and Reddel,R.R. (2008). The murine stanniocalcin 2 gene is a negative regulator of post-natal growth. Endocrinology. 149, 2403-2410.

Gunning,P., O'Neill,G., and Hardeman,E. (2008). Tropomyosin-Based Regulation of the Actin Cytoskeleton in Time and Space. Physiological Reviews 88, 1-35.

Macarthur,D.G., Seto,J.T., Chan,S., Quinlan,K.G., Raftery,J.M., Turner,N., Nicholson,M.D., Kee,A.J., Hardeman,E.C., Gunning,P.W., Cooney,G.J., Head,S.I., Yang,N., and North,K.N. (2008). An Actn3 knockout mouse provides mechanistic insights into the association between {alpha}-actinin-3 deficiency and human athletic performance. Hum.Mol.Genet. 17, 1076-1086.

O'Neill,G.M., Stehn,J., and Gunning,P.W. (2008). Tropomyosins as interpreters of the signalling environment to regulate the local cytoskeleton. Semin.Cancer Biol. 18, 35-44.

Schevzov,G., Fath,T., Vrhovski,B., Vlahovich,N., Rajan,S., Hook,J., Joya,J.E., Lemckert,F., Puttur,F., Lin,J.J., Hardeman,E.C., Wieczorek,D.F., O'Neill,G.M., and Gunning,P.W. (2008). Divergent regulation of the sarcomere and the cytoskeleton. J Biol.Chem. 283, 275-283.

Vlahovich,N., Schevzov,G., Nair-Shaliker,V., Ilkovski,B., Artap,S.T., Joya,J.E., Kee,A.J., North,K.N., Gunning,P.W., and Hardeman,E.C. (2008). Tropomyosin 4 defines novel filaments in skeletal muscle associated with muscle remodelling/regeneration in normal and diseased muscle. Cell Motil.Cytoskeleton 65, 73-85.

Creed,S., Bryce,N., Naumanen,P., Weinberger,R., Lappapainen,P., Stehn,J., and Gunning,P. (2008). Tropomyosin Isoforms define distinct microfilament populations with altered drug susceptibility. European Journal of Cell Biology. (In Press. Doi: 10.1016/j.ejcb.2008.03.004)

Invited Reviews

Gunning,P., Weinberger,R., and Jeffrey,P. (1997). Actin and tropomyosin isoforms in morphogenesis. Anatomy & Embryology 195, 311-315.

Gunning,P., Hardeman,E., Jeffrey,P., and Weinberger,R. (1998). Creating intracellular structural domains: spatial segregation of actin and tropomyosin isoforms in neurons. Bioessays 20, 892-900.

Gunning,P., Weinberger,R., Jeffrey,P., and Hardeman,E. (1998). Isoform sorting and the creation of intracellular compartments. Annual Review of Cell & Developmental Biology 14, 339-372.

Gunning,P. (2003). Protein Isoforms and Isozymes. In Nature Encyclopedia of the Human Genome, D. N. Cooper, ed. (London: Nature Publishing Group), pp. 835-839.

Gunning,P.W., Schevzov,G., Kee,A.J., and Hardeman,E.C. (2005). Tropomyosin isoforms: divining rods for actin cytoskeleton function. Trends in Cell Biology 15, 333-341.

Stehn,J.R., Schevzov,G., O'Neill,G.M., and Gunning,P.W. (2006). Specialisation of the tropomyosin composition of actin filaments provides new potential targets for chemotherapy. Curr.Cancer Drug Targets. 6, 245-256.