Mantamadiotis laboratory: Cancer signalling

Research Overview

Specific interests and expertise includes investigations into transcriptional and signalling networks involved in neuronal development, neural stem cells and brain cancer stem and tumour cells. The laboratory also has an interest and expertise in the design and use of novel animal models of human nervous system pathology.

Signalling pathways 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.

Scheme showing the CREB signalling pathway

Figure 1: The CREB signaling pathway is a major focus of our laboratory. The CREB transcription factor is at the hub of a variety of signaling pathways. Our lab focus is on the physiological outcomes of perturbations in factors within the CREB pathway, at the level of the whole organism.

Recent work has also focussed on novel links between the PI3K pathway and the CREB pathway. In collaboration with Prof Wayne Phillips, Peter MacCallum Cancer Centre, we have generated a novel brain cancer mouse model carrying human-relevant PI3K pathway mutations to investigate the complex signaling networks regulating brain tumour development and growth and to test a range of novel PI3K inhibitors.

Scheme showing generation of conditional mutant mice

Figure 2: We use various animal models including conditional knockout mice generated by Dr Mantamadiotis while at the DKFZ, Heidelberg, Germany. These mice are available through the European Mutant Mouse Archive (EMMA).

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.

photo of mutant and control mice, showing smaller mutant mouse

histology of hypothalamus showing differences between normal and mutant mice

Figure 3: Mice with an nervous system specific KO exhibit dwarfism due to reduced levels of hypothalamic GHRH. see Ref 7

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.

Research Projects

The role of CREB in cancer

Delineation of transcriptional networks in stem and progenitor cells

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

Staff

Gulay Filiz, Research Assistant
Daniel Brown, PhD Candidate
Paul Daniel, PhD Candidate

Collaborators

National:

A/Prof Frederic Hollande, Department of Pathology, University of Melbourne
Dr Vicki Lawson, Department of Pathology, University of Melbourne
Prof Wayne Phillips, Peter MacCallum Cancer Centre
Prof Robert G. Ramsay, Peter MacCallum Cancer Centre
Drs Mirella Dottori & Giovanna D'Abaco, Centre for Neural Engineering, University of Melbourne
Dr Andrew Morokoff, Department of Surgery (Neuro-oncology Group), Royal Melbourne Hospital
Prof Timothy Cole, Department of Biochemistry and Molecular Biology, Monash University

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

Research Projects

This Research Group doesn't currently have any projects



Faculty Research Themes

Cancer

School Research Themes

Cancer, Cell Signalling



Key Contact

For further information about this research, please contact Dr Theo Mantamadiotis

Department / Centre

Pathology