Mantamadiotis Laboratory - Cancer Signalling
| Contact: | Dr Theo Mantamadiotis |
|---|---|
| Phone: | +61 3 8344 5861 |
| Fax: | +61 3 8344 4004 |
| Email: | theom@unimelb.edu.au |
Our research is aimed at unravelling transcriptional and signalling pathways regulating the survival, growth and differentiation of normal cells and cancer cells.
Key Research Areas
Specific interests and expertise includes the investigations into transcriptional and signalling networks involved in neuronal development, neural stem cells and brain cancer stem cells. The laboratory also has an interest and expertise in the design and use of novel animal models of human nervous system pathology.
The CREB signalling pathway in glioma biology:
Much of our effort has focused on understanding how the cAMP Responsive Element Binding (CREB) transcription factor controls neural progenitor cell survival and growth. Studies in transgenic mice and zebrafish have shown that the CREB pathway is important for neural progenitor cell survival and growth. This has led to the hypothesis that the same CREB-dependent mechanisms involved in normal neural progenitor cell survival and growth are also important to the survival and growth of brain tumour progenitor cells. Our laboratory is now investigating the CREB pathway in human brain tumour cells and tumour initiating cells.
Identification of novel genes involved in glioma cell signalling:
Gene expression profiling using massively parallel sequencing/next generation sequencing approaches of tumour cells is aimed at identifying molecular signatures and biomarkers which will help identify novel mechanisms contributing to tumour development and reveal novel drug targets.
Other work:
Collaborations with other research groups allows us to expand our interests to explore common molecular pathways having a role in the pathology of other cell systems/organs, such as the brain (psychosis, addiction, memory, behaviour), peripheral nervous system development, lung development and lung cancer.
Objectives
- To use an integrated approach to study the molecular and cellular changes in brain tumour cells
- To determine the role of the CREB transcriptional pathway in tumour biology
- To move toward more effective targeting of diseases such as brain cancer through pharmacological approaches
Major Achievements
- Identification of the CREB transcription factor as a key regulator of neuronal survival and neural stem cell survival and growth
- Identification of the CREB transcription factor as a potential biomarker of human glioma cells
- Design of novel transgenic mice allowing conditional disruption or overexpression of genes driving tumour development
Technology
- Molecular biology
- Cell biology - Stem cell culturing
- Transgenic and conditional mutant mouse design
Collaborations
National:
- Dr. Giovanna Dabaco – Department of Surgery (Neuro-oncology Group), Royal Melbourne Hospital
- A/Prof Timothy Cole – Department of Biochemistry and Molecular Biology, Monash University
- A/Prof Robert G. Ramsay – Peter MacCallum Cancer Centre
- A/Prof Louise Purton, St Vincent’s Institute
- A/Prof Martin van den Buuse - Melbourne Brain Centre (MHRI)
- Prof Andrew Lawrence - Melbourne Brain Centre (Florey Neurosci. Inst.)
International:
- Dr. Stavros Taravrias, Medical School, University of Patras, Greece
- Dr. George T. Stathopoulos, Medical School, University of Patras, Greece
- Prof. Günther Schütz, German Cancer Research Centre, Heidelberg, Germany
Funding
- The University of Melbourne: Department of Pathology
- National: ARC Project 2009-2011
- International: EU FP7 Marie Curie International Reintegration Grant 2009-2012
Recent Publications
- Mantamadiotis T, Papalexis N, Dworkin S. (2012) CREB signalling in neural stem/progenitor cells: Recent developments and the implications for brain tumour biology. BioEssays 34(4):293-300
- Kinross KM, Montgomery KG, Kleinschmidt M, Waring P, Ivetac I, Tikoo A, Saad M, Hare L, Roh V, Mantamadiotis T, Sheppard KE, Ryland GL, Campbell IG, Gorringe KL, Christensen JG, Cullinane C, Hicks RJ, Pearson RB, Johnstone RW, McArthur GA, Phillips WA. (2012) An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice. J Clin Invest. 122(2):553-7
- Madsen,H, Navaratnarajah,S, Farrugia,J, Djouma,E, Ehrlich,M, Mantamadiotis,T, Van Deursen,J, Lawrence,A. (2012) CREB1 and CREB binding protein in striatal medium spiny neurons regulate behavioural responses to psychostimulants. Psychopharmacology. 219(3):699-713=
- Bird,AD, Flecknoe,SJ, Tan,KH, Olsson,PF, Antony,N, Mantamadiotis,T, Hooper,SB, Cole,TJ. (2011) cAMP response element binding protein is required for differentiation of respiratory epithelium during murine development. PLoS One. 2011 Mar 8;6(3):e17843
- Mantamadiotis,T & Taraviras,S. (2011) Self-renewal mechanisms in neural cancer stem cells. Frontiers in Biosciences. 16:598-607
- Dworkin,S, Mantamadiotis,T. (2010) Targeting CREB signalling in neurogenesis, Expert Opinion On Therapeutic Targets. 14(8):869-79
- Dworkin,S, Malaterre,J, Hollande,F, Darcy,PK, Ramsay,RG, Mantamadiotis,T. (2009) CREB is required for mouse neural progenitor cell survival and expansion. Stem Cells, 27(6):1347-57
- McPherson,CS, Mantamadiotis,T, Tan,S-S, Iwasato,T, Lawrence,AJ. (2009) Deletion of CREB1 from the Dorsal Telencephalon Reduces Motivational Properties of Cocaine. Cerebral Cortex, Apr;20(4):941-52
- *Malaterre,J, *Mantamadiotis,T, Dworkin,S, Lightowler,S, Nichols,NR, Ransome,MI, Turnley,AM, Emambokus,N, Frampton,J, Ramsay,RG. (2008) c-Myb is required for neural progenitor cell proliferation and maintenance of the neural stem cell niche in adult brain. Stem Cells, 26(1):173-81
- Dworkin,S, Heath,JK, Malaterre,J, Hogan,BM, DeJong-Curtain,T, Ramsay,RG, Mantamadiotis,T. (2007) CREB regulates neural proliferation, midbrain-hindbrain organization and patterning in zebrafish. Dev. Biol. 147(2):373-87
- Spella,M, Britz,O, Kotandaki,P, Lygerou,Z, Nishitani,H, Ramsay,RG, Flordellis,C, Guillemot,F, Matamadiotis,T, Taraviras,S. (2007) Licensing regulators Geminin and Cdt1 identify progenitor cells of the mouse CNS in a specific phase of the cell cycle. Neuroscience 307(1):127-41
- Malaterre,J, Carpinelli,M, Ernst,M, Sutton,S, Alexander,W, Cooke,MP, Dworkin,S, Heath,JKH, Frampton,J, McArthur,G, Clevers,H, Hilton,D, Mantamadiotis,T, Ramsay,RG (2007) c-Myb is required for progenitor cell homeostasis in colonic crypts. Proc. Natl Acad. Sci. USA, 104: 3829-3834
- Mantamadiotis,T, Kretz,O, Ridder,S, Bleckmann,SC, Bock,D, Gröne,HJ, Malaterre,J, Dworkin,S, Ramsay,RG, Schütz,G (2006) Hypothalamic CREB loss causes anterior pituitary hypoplasia and dwarfism in mice. Mol. Endocrinol. 20(1):204-211
- Baumann,S, Kyewski,B, Bleckmann,SC, Greiner,E, Rudolph,D, Schmid,W, Ramsay,RG, Krammer,PH, Schütz,G, Mantamadiotis,T (2004) CREB function is required for normal thymic cellularity and post-irradiation recovery. Eur. J. Immunol., 34:1961-1971
- Mantamadiotis,T, Lemberger,T, Bleckmann,SC, Kern,H., Kretz,O, Martin-Villalba,A, Tronche,F, Kellendonk,C, Gau,D, Kapfhammer,J, Otto,C., Schmid,W, Schütz,G (2002) Disruption of CREB function in brain leads to neurodegeneration. Nature Genetics 31(1):47-54