Associate Professor Nicholas Saunders
Associate Professor Nicholas Saunders

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"Wonderment in nature."

That's how Associate Professor Nick Saunders describes what has driven his interest in science ever since a young age. This sense of wonder at the inner-workings of nature led him to the University of Western Australia (UWA) where he first studied anatomy and human biology, and then trained as a pharmacologist.

 

His PhD studies in pharmacology engendered a profound interest in the molecular sciences. Saunders wanted to learn more. He soon found an opportunity to do so when he was awarded a Fogarty Visiting Fellowship at the National Institute of Environmental Health Sciences (NIEHS) in the US.

It was there, in the laboratory of Professor Anton Jetten, that Saunders first began working on squamous epithelial cells. These cells are found on the outer layer of the skin and upper aerodigestive tract.  Saunders and Jetten were particularly interested in cell ‘differentiation’, which is the normal process by which cells mature and become specialised. By studying squamous cell differentiation in both normal and cancerous conditions, they wanted to identify the early triggers that cause things to go awry in Squamous Cell Carcinoma (SCC).  

SCC is a common form of skin cancer and accounts for approximately 90% of head and neck cancers. Saunders recognised that understanding differentiation in SCC is not only crucial to the development of new SCC therapeutics, it has even broader implications.  

“SCC has interesting biology," he explains. "It provides an opportunity to study the cancer process.”

Saunders and his NIEHS colleagues were able to begin painting a picture of the molecular players in SCC development and he quickly became an expert on keratinocytes, the epithelial cell type that comprises stratified squamous epithelia. This drew the interest Professor Ian Frazer at the University of Queensland’s Centre for Immunology and Cancer Research (CICR) and Saunders was offered the opportunity to establish an Epithelial Pathobiology Group at the CICR.  

Saunders is now an Associate Professor and Head of the Epithelial Cancer Division at the University of Queensland's Diamantina Institute (UQDI), and believes the unique relationship between UQDI and the Princess Alexandra Hospital is essential to the success of his research programs.  

"We try to engage in aspects of cancers that represent the biggest clinical challenge," he says. "We are entirely dependent on clinical collaborations. I couldn't do this work elsewhere."  

Since establishing his group at the UQDI Saunders’ interests have extended to lead active research in a number of different cancer types including SCC, osteosarcoma (OS), chronic lymphocytic leukaemia (CLL) and Breast cancer (BC). The common theme in all of his work is to focus on those patients who have incurable or drug resistant disease. In particular, he and his colleagues try to identify novel defects within these cancers that can be targeted by existing or recently developed classes of drugs. Over the years, his group has made several landmark findings which have led to the completion of three clinical trials, two current ongoing clinical trials, as well as three international patents.
 
Squamous Cell Carcinoma
The Saunders laboratory is internationally recognised as a leader in the field of SCC translational biology. In particular, A/P Saunders wants to exploit defects in cell differentiation in order to develop new diagnostics and therapeutics for SCC. A major step toward this goal relates to a protein called E2F, which is an essential component of normal cell development and growth.  Saunders and his colleagues found that E2F is produced at higher than normal levels in SCC, and when that happens, the cells lose the ability to regulate growth and proliferation. Saunders is investigating new anti-cancer strategies for SCC based on this discovery.   

Osteosarcoma
A/P Saunders is also particularly interested in another form of cancer called osteosarcoma, the most common form of paediatric bone cancer. He and colleague, Dr Endo-Munoz, previously discovered that the loss of bone cells called osteoclasts is what allows an osteosarcoma to metastasise to other organs such as the lungs. From this work, the team moved forward to discover at least 2 lead molecules that reduce metastases in preclinical models. As a result of these successful findings A/P Saunders and Dr Endo-Munoz have initiated a nationwide clinical trial of one of their lead molecules in dogs with osteosarcoma with their veterinary oncology colleagues. OS is a rare disease in humans but a common disease in large breeds of dogs so that trialling auronofin in dogs will provide clinical data quickly so that we can progress to human clinical trials.
 
Chronic Lymphocytic Leukaemia
Chronic Lymphocytic Leukaemia (CLL) is the most common adult leukaemia accounting for approximately 1,000 new cases per year in Australia and an accompanying mortality of approximately 300 patients per year (AIHW, 2009).  Unfortunately, for those patients who develop progressive disease, the prognosis is poor. These patients are treated with immunochemotherapy (eg Fludarabine, Cyclophosphamide and Rituximab), however this is not curative and these patients will eventually develop drug-resistant disease and die. Thus, there is a clinical need for more effective and less toxic therapies for patients with CLL.
Our team (A/P Saunders and Haematologist, A/P Devinder Gill) recently identified a novel mechanism that may explain the profound resistance to antibody therapies observed in patients with CLL. In particular, we have shown that therapeutic antibodies in current use for CLL cause leukaemic cell death by inducing a macrophage-dependent event (referred to as ADCC). Significantly, we have shown that leukaemic cells from patients with advanced disease develop resistance to therapeutic antibodies primarily because they lose function of biochemical pathways that normally activate a critical protein that interacts with immune cells. Without it, the antibodies can’t trigger a therapeutic immune response. However, we have shown that therapy resistance can be reversed with specific pharmacological inhibitors that target one of the proteins responsible for this. Thus, we have identified a novel process by which leaukaemic cells acquire drug resistance. Moreover, we have shown this an actionable target which can be exploited with existing and emerging therapeutics. This work is currently under review for publication. 
 
Breast Cancer
Our group has been actively working in the area of breast cancer research for a few years now. Our work focuses around a collaborative Unit of A/P Saunders, Dr Gannon, Prof Melissa Brown, and A/P Ian Bennett (breast cancer surgeon). 
Worldwide, breast cancer (BC) is the most common cancer affecting women. Despite the efforts of large multinational consortia, no clear genomic or heritable feature(s) can explain the high incidence of breast cancer. It is estimated that 16% of all human cancers have a known infectious cause. However, following a genomic and transcriptomic analysis of primary breast cancer samples collected at the Princess Alexandra hospital as well as a comprehensive interrogation of RNA-seq data available through the TCGA we can exclude an association between known human viruses and breast cancer (paper submitted). Emerging evidence is accumulating that bacterial communities within the gastro-intestinal (GI) tract contribute to various pathologies including cancer. Whilst our preliminary studies allow us to exclude known viruses as a cause of human breast cancer our preliminary data indicates that 70% of normal breast tissue contains a bacterial community whereas only 25% of breast cancer tissue has a bacterial community. Whilst our data do not define a causal relationship it is very clear that breast cancer tissue is associated with a very significant reduction in bacterial burden.  In this regard we are currently studying this association in more detail with a view to determine if these changes in bacterial communities could contribute to breast cancer formation or could be exploited as early markers of breast to complement existing diagnostics.


 

Email: nsaunders@uq.edu.au
Telephone: +61 7 3443 7091

Dr Anthony Dicker (past PhD student). Runs a skin cancer clinic in Melbourne and is a distance lecturer for UQ School of Medicine, Queensland.
Dr Magdelena Auret (past PhD student). Postdoctoral Fellow with Prof Nick Hayward (QIMR), Queensland.
Dr Rafael Erlich (past PhD student). Postdoctoral Fellow at CCRI, Sydney.
Dr Alexander Guminski (past Practitioner Fellow). Medical Oncologist at Royal North Shore Hospital and U Syd Ass Prof in Medicine, Sydney.

Open Access

UQDI Collection

All in UQ eSpace

Some select recent publications
 
  • Endo-Munoz L, Cumming A, Sommerville S, Dickinson I, Saunders NA. Osteosarcoma is characterised by reduced expression of markers of osteoclastogenesis and impaired antigen presentation compared to normal bone. Br. J. Cancer, 103(1):73-81, 2010.
  • Endo-Munoz L, Cumming A, Rickwood D, Wilson D, Cueva C, Ng C, Strutton G, Cassady I, Evdokiou A, Sommerville S, Dickinson I, Guminski A, Saunders NA. The loss of osteoclasts contributes to the development of osteosarcoma pulmonary metastases. Cancer Research. 70(18):7063-7072, 2010
  • Erlich RB, Kherrouche Z, Rickwood D, Endo-Munoz L, Cameron S, Dahler A, Rethinam M, Merida De long L, Guminski, Saunders NA. Dual PI3K-mTOR inhibitors and histone deacetylase inhibitors as a new therapeutic option for head and neck squamous cell carcinoma. Br. J. Cancer, 106:107-115, 2012.
  • Saunders NA, Simpson F, Thompson EW, Hill M, Endo-Munoz L, Leggatt G, Minchin RF, Guminski A. The role of intratumoural heterogeneity in cancer drug resistance: molecular and clinical perspectives. EMBO Mol. Med.,4:675-684, 2012,
  • Endo-Munoz L, Evdokiou A, Saunders NA. The role of tumour-associated macrophages and osteoclasts in osteosarcoma metastasis. BBA Rev. Cancer, 1826(2):434-442, 2012 
  • Cameron S, Merida de Long L, Hazar-Rethinam M, Topkas E, Endo-Munoz L, Cumming A, Gannon O, Guminski A, Saunders NA. Focal overexpression of CEACAM6 contributes to enhanced tumorigenesis in head and neck cancer via suppression of apoptosis. Mol Cancer, 11(1):74- 81, 2012. 
  • Gannon O, Merida De Long L, Endo-Munoz L, Hazar-Rethinam M, Saunders NA. Dysregulation of the repressive H3K27 trimethylation mark in head and neck squamous cell carcinoma contributes to dysregulated squamous differentiation. Clin Cancer Res. 19(2); 1–14., 2013,
  • Burgess M, Gill D, Singhania R, Reynolds B, Smith L, Mollee P, Cheung C, Chambers L, Saunders N* and McMillan N and. CD62L as a therapeutic target in chronic lymphocytic leukaemia. Clin Cancer Res., 19(20):1-11, 2013,  (*corresponding author)
  • Hazar-Rethinam M, Merida de Long L, Gannon O, Topkas E, Boros S, Vargas AC, Dzienis M, Mukhopadhyay P, Simpson F, Endo-Munoz L, and Saunders N. A novel E2F/Sphingosine kinase 1 axis regulates anthracycline response in squamous cell carcinoma. Clin. Cancer Res., 21(2):417-27, 2015.
  • Gannon OM, Merida de Long L, Hazar-Rethinam M, Topkas E, Endo-Munoz L,Thomas G, Zhang P, Saunders NA.  Confluence induced squamous differentiation is not accompanied by changes in H3K27me3 repressive epigenetic mark. J Invest Dermatol. 135(10):2446-2454, 2015.
  • Hazar-Rethinam M, Merida de Long L, Gannon O, Boros S, Vargas AC, Dzienis M, Mukhopadhyay P, N Saenz-Ponce, Dantzic DE, Simpson F, Endo-Munoz L, and Saunders N. RacGAP1 is a novel downstream effector of E2F7-dependent resistance to doxorubicin and is prognostic for overall survival in squamous cell carcinoma.  Mol Cancer Ther., 14(8):1939-1950, 2015.
  • Endo-Munoz L, Cai N, Cumming A, Merdia De long L, Topkas E, Loo D, Hill M, Pryce K, Mukhopadhyay P, Saunders N. A small molecule inhibitor of uPA blocks signaling in osteosarcoma tumour cells and the bone microenvironment and inhibits pulmonary metastasis. PLosOne, 10(8):e0133592, 2015
  • Topkas E, Ca N, Cumming A, Hazar-Rethinam M, Gannon OM, Burgess ML, Saunders NA, Endo-Munoz L.   Auranofin as a novel therapy for targeting thioredoxin reductase in metastatic osteosarcoma.  Oncotarget, 7(1):831-44. 2016
  • Gannon OM, Antonsson A, Milevskiy M, Brown MA, Saunders NA*, Bennett IC. No association between breast cancer and expression of human papilloma viral transcripts.  Scientific Reports, 14(5):18081. 2015 * corresponding author
  • Burgess M, Ellis JJ, Mapp S, Mollee P, Mazzieri R, Mattarrollo S, Gill D, Saunders NA. Transcriptomic analysis of monocytes and macrophages derived from CLL patients which display differing abilities to respond to therapeutic antibody immune complexes. Genomics Data, 8:4-6, 2016.
  • Gannon OM, Merida DeLong L, Saunders NA. DUX4 is derepressed in late-differentiating keratinocytes in conjunction with loss of H3K9me3 epigenetic repression. J. Invest. Dermatol., 136(6):1299-1302, 2016.
  • Macklin R, Wang H, Loo D, Martin S, Cumming A, Cai N, Lane R, Topkas E, Inder K, Saunders NA, Endo-Munoz L.  Extracellular vesicles secreted by highly metastatic clonal variants induce metastatic behavior in poorly metastatic clones.  Oncotarget, In Press.
  • Burgess ML, Mapp S, Mazzieri R, Ellis J, Cheung C, Chambers L, Mattarollo S, Mollee P, Gill D, Saunders NA.  Increased FcgRIIb-dominance contributes to the emergence of resistance to therapeutic antibodies in chronic lymphocytic leukaemia patients. Oncogene, In Press.


 

 

 

The research focus of my laboratory revolves around identifying the molecular processes underlying advanced/incurable cancers with a view to exploiting this knowledge in the development of new therapeutic strategies. 
 
In particular, I have active interests in
 
i) squamous cell carcinoma,
ii) osteosarcoma,
iii) chronic lymphocytic leukaemia and
iv) breast cancer.
 
These interests are multidisciplinary in nature and highly collaborative.

 

Squamous differentiation and SCC
  • Defining the E2F7/SK1/S1P/AKT axis in SCC and its role in drug resistance
  • The use of phylogenetic mapping to define tumour evolution during tumour formation and in response to drug therapies  in SCC
  •  Defining the role of Dux 4 in terminal phases of squamous differentiation
  • Translating EGFR trafficking status into new treatments in SCC
Osteosarcoma
  • Auranofin as a potent antimetastatic agent in osteosarcoma
  • The role of exosomes in osteosarcoma metastasis
  • Defining the role of DCBLD2 overexpression in osteosarcoma metastasis.
Chronic lymphocytic leukaemia
  • Mapping the defects in the FcgR network that exists in CLL patients with progressive disease
  • Identifying mechanisms to overcome resistance to therapeutic antibodies in chronic lymphocytic leukameia
Breast Cancer
  • Profiling the interstitial microbiome in primary breast cancer tissue


 

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