Hulett - Inflammation and tumour progression
Our research focuses on defining key molecular mechanisms that drive tumour progression, inflammatory disease and innate immunity. In particular, we aim to understand the mechanisms and function of innate defense peptides and the heparan sulphate-degrading enzyme heparanase in immunity and tumour progression, in order to develop novel therapeutics to treat infection, inflammatory disease and cancer.
Our interests are focused on two main research themes (i) to define the molecular basis of membrane-targeting by defensins, its importance in innate defense, and to use this information to design and develop novel antimicrobial and anticancer molecules, and (ii) to investigate the role of heparanase and its drug-targeting in the important inflammatory disease setting of atherosclerosis and also in immune surveillance of breast and prostate carcinoma.
Heparanase function in tumour metastasis and inflammatory disease
The ability of malignant tumour cells to escape from primary tumour sites and spread through the circulation to other sites in the body (metastasis) is what makes cancer such a deadly disease. An essential process in metastasis is cell invasion – where tumour cells move into and out of the vasculature. Cell invasion is also a critical event in the migration of white blood cells of the immune system (leukocytes) to sites of inflammation to combat infections. The heparan-sulphate (HS)-degrading enzyme has been shown to play a key role in the degradation of extracellular matrices and its activity strongly correlates with the metastatic capacity of tumour cells and the migratory capacity of leukocytes. We have shown that heparanase is the dominant HS-degrading enzyme in mammalian tissues, making it an attractive drug target.
We are currently working towards:
- Further understanding the molecular basis of heparanase function at the structural level.
- Defining the dysregulation of heparanase gene expression in cancer and inflammatory disease.
- Using heparanase conditional knockout mice in disease models to define the precise role and contribution of heparanase in tumour progression and inflammation (Putz et al., 2017, Poon et al., 2014).
Innate defense molecules as anti-cancer agents
Defensins are innate immunity proteins involved in host protection against pathogens. We have identified a subfamily of defensins that show promise as antimicrobial and anti-cancer agents (Järvå et al., 2018, Järvå et al., 2018, Kvansakul et al., 2016, Baxter et al., 2015, Poon et al., 2014).
We have extensive programs dedicated to:
- Defining the molecular basis of the antimicrobial and anticancer activity of defensins using a range of biochemical and biophysical methods including live cell imaging, electron microscopy, X-ray crystallography and small-angle X-ray scattering (in collaboration with Dr Marc Kvansakul).
- In vitro and In vivo testing of defensins in cell and mouse models of infection, tumour growth and progression.
Histidine-rich glycoprotein in necrotic cell/pathogen clearance and autoimmunity
Histidine-rich glycoprotein (HRG) is an abundant multi-functional plasma protein of vertebrates. We have shown HRG is a novel pattern recognition molecule that forms an adaptor complex with other innate immunity molecules to mediate the clearance of necrotic cells through phagocytes. Based on these observations we propose that HRG plays a key role in maintaining efficient clearance of necrotic cells from the circulation, a critical process of the innate immune system for the elimination of self-antigens to prevent autoimmune disease. In addition, we have observed striking similarities between the recognition of necrotic cells and pathogens by the innate immune system. We propose that the same molecular mechanisms are used to clear these potentially harmful materials and promote the resolution of tissue injury (Priebatsch et al., 2017, Patel et al., 2013, Poon et al., 2011 ).
We are currently working on:
- Defining the in vivo role of HRG in necrotic cell clearance using HRG deficient mice.
- Investigating the role of HRG in pathogen recognition and clearance.
- Defining the HRG complex for the recognition of necrotic cells and pathogens.
Apoptotic cell clearance
Research lead: Dr Ivan Poon
Billions of cells undergo apoptosis daily as part of homeostasis in the adult human. It is crucial that free apoptotic cells are readily cleared as the accumulation of apoptotic cells has been linked to numerous disease states such as inflammation, autoimmunity, cancer and infection. Thus, understanding the molecular basis of apoptotic cell removal will provide new avenues for therapeutic intervention
Prior to the recruitment and recognition by phagocytes, apoptotic cells often undergo a number of distinct morphologic changes. These changes in turn allow an apoptotic cell to be efficiently cleared by phagocytes. For instance, apoptotic cells can disassemble into discrete subcellular membrane-bound particles (1-5 μm) known as apoptotic bodies. The generation of these 'bite-size' apoptotic bodies can facilitate their uptake and processing by phagocytes. However, the precise molecular machinery that control the quantity and quality of apoptotic bodies is not well-defined. We propose that regulated apoptotic bodies formation during cell death is essential for the prompt removal of apoptotic cells. Importantly, modulating the mechanism of apoptotic bodies formation could alter the consequence of corpses clearance in health and disease (Atkin-Smith et al., 2017, Atkin-Smith et al., 2015, Poon et al., 2014).
Meet the team
Novel plant defensins and their use in the treatment of proliferative diseases: WO 2013/056309 A1
Novel forms of plant defensins: WO 2013/056308
Treatment of proliferative diseases: AU 2011/269726
Treatment of proliferative diseases: WO 2011/160174 A1