Mantamadiotis laboratory: Brain Cancer Molecular Biology

• 
  
  Dr Theo Mantamadiotis

  theom@unimelb.edu.au

  View researcher's webpage

  +61 3 85597065

Research Overview

Specific interests and expertise includes investigations into transcriptional and signalling networks involved in neuronal development, neural stem cells and brain tumour cells. The laboratory also has an interest and expertise in the design and use of novel animal models of human nervous system pathology. Gene expression profiling using massively parallel sequencing/next generation sequencing approaches of glioma 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.

Signalling pathways in malignant brain cancer

Malignant brain cancers are amongst the most difficult to treat cancers, affecting people at any age. For the most common and deadly type of brain cancer, glioblastoma (grade IV glioma), prognosis is very poor and treatment options limited. Much of our effort has focused on understanding how aberrant activation of key cellular signal transduction pathways, including PI3K, MAPK and cAMP signalling changes tumour cell behaviours. Recent discoveries by our laboratory show that the PI3K pathway is a key driver of carcinogenesis in brain. Using engineered mice targeting PI3K mutations in neural stem/progenitor cells led to the development of fast growing aggressive glioma-like tumours. By deleting the transcription factor CREB specifically in the tumour cells, the same study revealed that CREB is a key transcriptional regulator of tumour growth and a potentially novel candidate for targeting in glioma patients.

Other work focuses on how to use already approved drugs to complement and enhance standard brain cancer treatments. For this, we are investigating the molecular mechanisms around the role of the cAMP pathway, the hyperactivation of which leads to expression of the death protein Bim, and the apoptosis of glioma cells.

With collaborators at the Peter Doherty Institute and the Peter MacCallum Cancer Centre we are examining the immunobiology of malignant brain cancer to enable the development of brain tumour-specific targeted immunotherapy in glioma patients.

Figure 1:A developing tumour in the brain of a mouse model of human brain cancer (Daniel et al., 2018, Neuro-oncology; https://doi.org/10.1093/neuonc/noy068)

STUDENT RESEARCH PROJECTS

We have potential projects for suitably qualified scientists, focussing on brain cancer, using techniques involving molecular biology, genomics, immunology and computational biology at Honours, Masters and PhD level students.

Staff

Marija Dinevska, PhD Student
Liam Furst, MBiomed

Collaborators

National:

• Prof Fabienne MacKay, School of Biomedical Sciences, University of Melbourne
• A/Prof Paul Neeson, Peter MacCallum Cancer Centre
• A/Prof Phil Darcy, Peter MacCallum Cancer Centre
• Prof Wayne Phillips, Peter MacCallum Cancer Centre
  Prof Robert G. Ramsay, Peter MacCallum Cancer Centre
• A/Prof Frederic Hollande, Department of Clinical Pathology, University of Melbourne
  Dr Vicki Lawson, Department of Immunology & Immunology, University of Melbourne
  Dr Andrew Morokoff, Department of Surgery, Royal Melbourne Hospital
• Dr Staley Stylli, Department of Surgery, Royal Melbourne Hospital

International:

• A/Prof George T Stathopoulos, University of Patras, Greece & CPC at Helmholtz Zentrum München, Munich, Germany
• A/Prof Stavros Taraviras, University of Patras, Greece
• Dr Erich Greiner, Cedrus Therapeutics, Hamburg, Germany

Funding

• CASS Foundation Medicine/Science Grants
• Brain Foundation Australia

Research Publications

(For a complete listing link to Pubmed)

1. NGUYEN HPT,DANIEL PM, FILIZ G, MANTAMADIOTIS T. 2018. Investigating neural stem cell and glioma stem cell self-renewal potential using extreme limiting dilution analysis (ELDA). Bio-Protocol, 8(17) Sep 5
2. DANIEL PM, FILIZ G, TYMMS MJ, RAMSAY RG, KAYE AH, STYLLI SS, MANTAMADIOTIS T. 2018. Intratumor MAPK and PI3K signaling pathway heterogeneity in glioblastoma tissue correlates with CREB signaling and distinct target gene signatures. Exp Mol Pathol, 105(1):23-31.
3. DANIEL P, FILIZ G, BROWN DV, CHRISTIEM, WARINGPM, ZHANGY, HAYNESJM, POUTONC, FLANAGAND, VINCANE, JOHNSTG, MONTGOMERYK, PHILLIPS WA, MANTAMADIOTIS T. 2018. PI3K Activation in Neural Stem Cells Drives Tumorigenesis which can be Ameliorated by Targeting the cAMP Response Element Binding (CREB) Protein,Neuro-oncology, doi:10.1093/neuonc/noy068
4. BROWN DV, FILIZ G, DANIEL P, HOLLANDE F, DWORKIN S, AMIRIDIS S, KOUNTOURI N, NG W, MOROKOFF A, MANTAMADIOTIS T. 2017. Expression of CD133 and CD44 in glioblastoma stem cells correlates with glioblastoma cell proliferation, phenotype stability and intra-tumor heterogeneiety. PLoS One, 12(2): e0172791.
5. MANTAMADIOTIS T. 2017. Towards targeting PI3K-dependent regulation of gene expression in brain cancer. Cancers, 9(6):60; doi:10.3390/cancers9060060.
6. DANIEL P, FILIZ G, MANTAMADIOTIS T. 2016. Sensitivity of GBM cells to cAMP agonist-mediated apoptosis correlates with CD44 expression and agonist resistance with MAPK signaling. Cell Death & Disease, 7(12): e2494.
7. BROWN DV, DANIEL P, D'ABACO G, GOGOS A, NG W, MOROKOFF A, MANTAMADIOTIS T. 2015. Coexpression analysis of CD133 and CD44 identifies Proneural and Mesenchymal subtypes of Glioblastoma Multiforme, Oncotarget, 6(8):6267-6280
8. DANIEL P, FILIZ G, BROWN DV, HOLLANDE F, GONZALES M, D’ABACO G, PAPALEXIS N, PHILLIPS WA, MALATERRE J, RAMSAY R, MANTAMADIOTIS T. 2014. Selective CREB-dependent cyclin expression mediated by the PI3K and MAPK pathways supports glioma cell proliferation, Oncogenesis, 3: e108
9. BROWN DV, MANTAMADIOTIS T. 2014. Insights into the next generation of cancer stem cell research, Frontiers in Biosciences (Landmark Ed.) 19(7):1028-1040
10. 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