Sam Faulkner, Nathan Griffin, Xiang Li, Alison Rutledge
The group works on the crosstalk between nerves and cancer cells, and the impact on tumour progression.
Until recently it was thought that neurons were not actively involved in cancer. However, recent evidence in prostate and breast cancers, including from our group, have shown that nerves promote tumour progression and that denervation can suppress both the development of the primary tumour and the outburst of metastases.
The objective of the group’s research is to identify the molecular mediators of the crosstalk between nerve and cancer cells, which constitute new and innovative biomarkers and therapeutic targets in oncology.
The methodologies used include analysis of human tumour samples, cell cultures, in vivo experiments and proteomic analysis.
The group work in collaboration with neurobiologists, pathologists, clinicians and private companies to translate the results of the research into practical outcomes in oncology.
Nerve-cancer cell crosstalk. Nerves infiltrate solid tumours and stimulate cancer growth and metastasis through the liberation of neurotransmitters.
Conversely, nerve infiltration in the tumour is mediated through the liberation of neurotrophic growth factors by cancer cells. Neurotransmitters and neurotrophic growth factors also impact angiogenesis and inflammation.
This reciprocal interaction fuels cancer development, and participates in cancer pain.
Pedro Garcia Sobrinho, Alice Kunzler
The focus of the group’s work has been the enzyme tyrosine hydroxylase which controls the rate of synthesis of the catecholamines dopamine, noradrenaline and adrenaline.
They have examined the role of regulation of tyrosine hydroxylase in response to different types of stress.
Their work is now focused on how regulation of tyrosine hydroxylase plays a role in Parkinson's disease.
They found that there is a selective loss of one of the human TH isoforms in Parkinson's disease and that expression of particular TH isoforms may render the cells more susceptible to death in Parkinson's disease.
Current work has focused on the role of infection and inflammation in the development and progression of Parkinson’s disease.
They found that there is a chronic activation of tyrosine hydroxylase in response to infection that only occurs in the dopaminergic neurons of the substantia nigra.
This may explain the capacity of infection processes to cause selective degeneration of the dopaminergic neurons of the substantia nigra that is a key feature of Parkinson’s disease.
The research area is the molecular mechanisms responsible for regulating neuronal function during development, plasticity and ischaemic/excitotoxic damage.
The main research focus is on the role and regulation of the important regulatory enzyme CaMKII.
The group have identified a new mechanism (autophosphorylation of CaMKII at T253) that controls the function of CaMKII in vivo through molecular targeting.
The group have shown that this mechanism regulates cell proliferation and is selectively activated in brain tissue by ischaemia and excitotoxity.
The current research explores the mechanisms by which this new regulatory mechanism controls cell death in the brain following stroke and the therapeutic potential of drugs that interfere with this regulatory mechanism.
Jie Zhong Chen
Hessam Tabatabaeehatambakhsh, Jennifer Latham, Simonne Sherwin, Amanda Croft
Xu Guang Yan
Chun Yan Wang, Yuan Yuan Zhang, Jia Yu Wang, Hamed Yari, Ting La, Su Tang Guo
Fu Xi Lei, Fen Liu
Melanoma is the most serious form of skin cancer that is often referred to as Australia's national cancer as Australia has the highest incidence of melanoma in the world.
However, there is currently no curative treatment once the disease spreads beyond the original site.
To address this major Australian health problem, the laboratory has been working on translational melanoma research with a focused theme of “overcoming resistance of metastatic melanoma to treatment”.
Specifically, the group are working on overcoming resistance of melanoma cells to programmed cell death induced by newly developed targeted therapeutic drugs and immunotherapeutic agents.
The group have initiated a number of new projects that advance the frontier of melanoma research.
These include “apoptosis-regulating long non-coding RNAs in melanoma”, “targeting resistance mechanisms of quiescent melanoma cells to programmed cell death”, “co-targeting CD47 and the MAPK pathway or PD-1/PD-L1 in the treatment of melanoma”, and “regulation of immune checkpoints in melanoma”.
Sharon Hollins, Joshua Atkins, Michael Geaghan, Ebrahim Mahmoudi, Dylan Kiltchewskij-Brown
The human brain is by far the most complex of organs, with around 100 billion neurons interconnected by up to 1000 trillion synapses.
During development, the formation, position and connectivity of these cells is precisely regulated and yet remain responsive to external sensory input and output from internal processing.
The group is interested in understanding the molecular systems that regulate neural development and synaptic plasticity so they can identify the underlying molecules and mechanisms that orchestrate the formation and behaviour of neural circuits.
These circuits provide the physiological basis of neural activity-associated logic, and their structure and plasticity is the foundation for a life-long capacity for learning and cognition.
These systems are sensitive to genetic and environmental influences, and a complex combination of these neurodevelopmental challenges can lead to neurocognitive and neuropsychiatric disorders such as schizophrenia.
By investigating the molecular neurobiology of these complex systems, and the syndromes that interfere with their normal function, the group has the potential to better understand human brain development and function.
These steps also provide a strong basis for developing biomarkers of brain disease and novel therapeutic strategies to defeat the most devastating neurocognitive disorders.
In 2015 the group made important methodological and theoretical advances that support their investigation of the complex systems biology of neurodevelopment, synaptic function and schizophrenia.
To explore the role of schizophrenia-associated miRNA in vivo the group have successfully implemented lentiviral transduction of the rat brain (collaboration with Chris Dayas and Rohan Walker) and observed schizophrenia-related neurobehavioural phenotypes.
They have also been developing a framework for high-resolution translational genomics using whole genome sequencing and applying this for personalised analysis of schizophrenia patients using integrated systems biology.
This research has made spectacular progress through the support of a NSW Health Collaborative Genomics Grant ($800,000), which enabled the group to sequence the entire genome of 500 participants in the Australian Schizophrenia Research Bank.
Further refinement in their understanding of the function of non-coding variants is being achieved through the development of isogenic cell lines produced through RNA-guided genome editing using the Cas9/CRISPR approach.
Support for this initiative was obtained from the US Brain and Behavioural Research Foundation, Independent Investigator Grant (US $100,000).
Ritambhara Aryal, Mohitosh Biswas, Nilofar Daneshi, Kristy Martin, Al Shahandeh, Jason Woods, Khadem Ali (co-sup.)
Melissa Baldwin, Cassandra Bower, Sam Gerami, Ryan Horn, Will Myles
The laboratory research applies omics and bioinformatics as well as more traditional cellular, molecular and functional approaches to understand central nervous system health and disease.
The group have had two major papers accepted on iron-myelin interactions in brain degenerative and psychiatric conditions following requests to collaborate on projects by researchers from University College London and UK Brain Expression Consortium.
The group are also working with pharmacy and other academics and industry stakeholders to align research and education for responsible delivery of precision medicine in healthcare practice.
A/Professor Milward attended two advisory group meetings for the US NIH Precision Medicine Initiative (Nashville; Intel, San Francisco) and chaired the ‘Big Data, Personal Genomics and Bioinformatics’ stream of the Global Precision Medicine Congress, London, September 2015.
In 2015 the laboratory had 1 PhD completion (Moones Heidari), 5 confirmations (Ali, Aryal, Biswas, Martin, Shahandeh) and new PhD student Jason Woods was awarded a Vice Chancellor’s Excellence Scholarship. Moones Heidari won the School Paper of the Year award and Ritu Aryal, Moones Heidari and Jason Woods all received Beautiful Science awards.
In 2015, the group had 8 papers and 1 encyclopaedia chapter accepted for publication with 3 international presentations (Milward University College London and University of Warwick, UK; Shahandeh, International BioIron Society, Hangzhou, China) and 20 posters at 1 international and 4 national conferences.
Manish Kumar, Shafiq Syed, Jyoti Goad, Ayesha Ali, Preety Bajwa, Subhransu Sahoo, Prathima Nagendra, Arnab Ghosh, Mariam Adebayo, Lisa Sercombe, Yazmin Crossingham
The major focus of the group’s research program is to develop new drugs for the treatment of gynaecological cancers (ovarian and uterine cancers).
The group are using genetically modified mouse models, cancer patient derived xenograft models and primary human tissue samples to define the molecular and cellular events involved in carcinogenesis and then using this knowledge to develop targeted therapies to improve clinical outcomes in human patients.
The current research focuses on:
- Role of microenvironment in ovarian and uterine cancers
- Wnt-P13K-mTOR signalling axis in ovarian and uterine cancers
- Cancer stem cells in ovarian and uterine cancers
- Circulating tumour cells in ovarian and endometrial cancer
- Pathogenesis of germ cell tumours
This work showed that loss of tumour suppressor genes guarding the mTOR pathway occurs, at both genomic and protein level, in ~60% of human serous ovarian cancer patients and similar alterations in mice also causes the development of serous ovarian cancer.
The group are investigating novel signal transduction pathways that control how breast cancer and leukaemia cells proliferate, metastasise and develop resistance to chemotherapeutics, with a view to developing new anti-cancer therapies that target these pathways that are less toxic than existing treatments.
In recent years, they have made several significant discoveries, and identified a novel target and therapeutic inhibitor that is effective in a range of cancer types (whilst leaving normal cells untouched), including acute myeloid leukaemia and childhood acute lymphoblastic leukaemia, breast cancer, and glioma.
The group have shown that this inhibitor significantly reduces tumour burden and increases survival times in mouse models of acute leukaemias, and outperforms existing gold standard treatments for these cancers.
This inhibitor is currently being commercialised by Newcastle Innovation.
As the overarching aim is to improve patient quality of life, they are also focused on developing novel methods of determining prognosis and ways of stratifying patient outcome following administration of existing treatments, so that a more personalised approach for cancer treatment can be developed.
In addition to the group’s drug discovery interests, they use a variety of proteomic and molecular techniques to identify novel biomarkers that can be used for the improved treatment of leukaemias, breast and prostate cancers.
Richard Kahl, Hayley Flanagan
Heather Murray, David Skerrett-Bryne, Abdul Mannan, Dr Jon Sillar, Nikita Panicker
The Molecular Oncology Group is part of The University of Newcastle’s Priority Research Centre for Cancer Research, Innovation and Translation, The Hunter Medical Research Institute Cancer Research Program and The Hunter Cancer Research Alliance.
The group also collaborate closely with the Human Genetics Department, KU Leuven and the Department of Biochemistry and Molecular Biology, University of Southern Denmark.
The research focuses on the molecular basis of cancer development, progression and chemotherapy resistance through the development of sophisticated in vitro and in vivo cancer model systems and world leading technologies.
The research program utilises both targeted (targeting tumour suppressor proteins, cellular metabolism and DNA damage) and non-targeted (unbiased comparative and quantitative proteomics) approaches.
The group employ high resolution techniques to complement these approaches such as multiplexed targeted proteomics (parallel reaction monitoring (PRM)), targeted next generation sequencing (NGS), and drug development pipelines incorporating advanced proteogenomic technologies.
In 2015 Dr Matt Dun was elected to the board of directors of the Australian Society for Medical Research, where he now sits as the National Media Director.
Brendan Scott, Chris Stevens, Andrew Novak
The laboratory research is centred on the roles inflammation and oxidation play in the development of chronic diseases.
The main focus is on periodontal disease and its function as a risk factor in many chronic diseases such as coronary heart disease, rheumatoid arthritis and type II diabetes.
One area of research is focused on activated complement proteins, specifically C5a, and it’s role as an anaphylatoxin and chemoattractant for neutrophils in rheumatoid arthritis patients.
In addition, this research is investigating nutritional modulation of the inflammatory cascade and antioxidant capacity, with the goal of identifying key dietary factors and their effects on reducing chronic inflammation and increasing systemic antioxidant capacity.
The group’s research also involves the role exercise plays in reducing chronic inflammation and increasing antioxidant capacity.
Current studies include the effects of activity levels on systemic inflammatory markers, plasma and saliva antioxidant capacities, white blood cell counts and their relationship to chronic disease states in a large cohort.
Joshua Brzozowski, Helen Jankowski
Danielle Bond, Crystal Naudin
Co-supervised Students (FScIT)
Benjamin Munro (PhD), Melanie Predebon (Honours)
The research focus is on improving cancer patient outcomes and quality of life.
The research seeks to achieve this by unravelling the role of extracellular vesicles in the process of metastasis.
Through characterising the make-up of these extracellular vesicles the group hope to identify a biomarker as well as a means to target the delivery of current chemotherapeutics specifically to cancer cells.
In collaboration with other local, national and international researchers they are also searching for more effective anti-cancer agents that are hidden within a biodiverse range of organisms.
- Identify a molecule within human body fluids that can predict disease and/or disease outcome for cancer patients
- Improve patient quality of life through the generation of targeted delivery of treatment and the development of novel treatments for cancer patients