EMPathy Breast Cancer Network: Chief Investigator Biographies
Prof Erik (Rik) Thompson was among the first to study the role of epithelial mesenchymal transition (EMT) in breast cancer, and he is a longstanding proponent of epithelial mesenchymal plasticity (EMP) as an important cancer process through focused articles (e.g. Cancer Research 65: 5991-5995 discussion p. 5995, 2005; JCB 172: 973, 2006; Nature Medicine "News and Views" 17: 1048, 2011; Nature (Bryce)). He founded the EMPathy Breast Cancer Network (EMPathy BCN) with an NBCF-supported think tank in 2008, which led to a successful bid for NBCF National Collaborative Research Program support for a research program that seeks to reduce mortality in breast cancer by targeting EMP. Although EMP dominates his research program, he has also established a collaborative research program on mammographic density that interfaces with radiologists, surgeons, pathologists and medical oncologists through the breast multidisciplinary meeting at St Vincent's Hospital (SVH)., and has maintained a research program into the potential targeting of MMP13 in breast cancer, building on long term experience in the MMP area. Rik has served on various grant review panels, serves on a number of editorial boards including Clinical and Experimental Metastasis, The Breast Journal and Cancer Microenvironment, and is Associate Editor (Epithelial Plasticity) for Cells Tissues Organs. He has 151 peer-reviewed primary publications and 51 reviews, book chapters and editorials - many in breast cancer.
Rik's long-standing commitment to the field of invasion and metastasis is also evident on an organisational level. He is the current President of the EMT International Association (TEMTIA), having co-founded TEMTIA (2003) and served as Treasurer (1993-2011) and Vice President (2011-2013). He has been co-convenor or organizing committee member for all TEMTIA meetings since 2003, including co-convenor of TEMTIA-I in 2003 and TEMTIA-V in 2011, and he will convene the TEMTIA-VII meeting in Melbourne in 2015. He was the founding president (2004-2007) of the Australasian Microarray and Associated Technologies Association (AMATA; no Australasian Genomic Technologies Association / AGTA), and has served as President of the Matrix Biology Society of Australia & New Zealand (2001-2003). As then President of the (International) Metastasis Research Society (MRS), he convened the 14th bienniel MRS conference in Brisbane in September 2012. In 2011 he initiated the first meeting of OzMRS, the Australasian chapter of MRS that functions as an interest group for metastasis researchers in Australia.
Since returning to Australia in 1997 after 11 years at the NIH and Georgetown University, USA, Rik has headed the Invasion and Metastasis Unit at St. Vincent's Institute (SVI) / University of Melbourne Department of Surgery at SVH (UM-DOS-SVH) (1997-2014). He served as Associate Director of SVI (1999-2002), Director of Research of the O'Brien Institute (2002-2006), and Director of Basic Science Studies at UM-DOS-SVH (2012-2014). He is currently Professor in Breast Cancer Research, School of Biomedical Sciences / Institute of Health and Biomedical Innovation at Queensland University of Technology, where he also serves as the Theme Leader for Chronic Disease and Ageing.
Key Achievements and Awards
- Creation of the EMPathy BCN network as an actively funded and engaged national collaborative team with a structured approach to new advances in breast cancer diagnosis and therapy
- Demonstration that specific MMP13-targetting agents have efficacy in experimental breast cancer and bone-metastasised lesions, and may have translational potential
- Establishment of the biology theme for a multidisciplinary research program into the molecular and cellular underpinnings of the breast cancer risk associated with increased mammographic density
- Matrix Biology Society of Australia and New Zealand Barry Preston Award (2001)
- NBCF Pink Circle Research Award (2010)
Felicity M. Davis, Teneale A. Stewart, Erik W. Thompson, Gregory R. Monteith. Targeting EMT in cancer: opportunities for pharmacological intervention. Trends in Pharmacological Sciences 1152 (2014).
Purdom E, Restall C, Busuttil RA, Schluter H, Boussioutas A, Thompson EW, Anderson RL, Speed TP, Haviv I. Determining epithelial contribution to in vivo mesenchymal tumour expression signature using species-specific microarray profiling analysis of xenografts. Genet Res (Camb) 95: 14-29 (2013)
Davis FM, Parsonage MT, Cabot PJ, Parat M-O, Thompson EW, Roberts-Thomson SJ, Monteith GR. Assessment of gene expression of intracellular calcium channels, pumps and exchangers with epidermal growth factor-induced epithelial-mesenchymal transition in a breast cancer cell line. Cancer Cell Int. 13:76 (2013)van Denderen BJW, Thompson EW. Cancer: The to and fro of tumour spread. Nature "News and Views" 493: 487-488 (2013)
Pinto CA, Widodo E, Waltham M, Thompson EW. Breast cancer stem cells and epithelial mesenchymal plasticity implications for chemoresistance. Cancer Letters 341:56-62 (2013)
Bonnomet A, Syne L, Brysse A, Feyereisen E, Thompson EW, Noël A, Foidart J-M, Birembaut P, Polette M, Gilles C. A dynamic in vivo model of epithelial-to-mesenchymal transitions in circulating tumor cells and metastases of breast cancer. Oncogene 31:3741-53 (2012)
Gunasinghe NPAD, Wells A, Thompson EW, Hugo HJ. Mesenchymal-epithelial transition (MET) as a mechanism for metastatic colonisation in breast cancer. Cancer Met. Rev. 31:469-78 (2012)
Raviraj V, Zhang H, Chien H, Cole L, Thompson EW, Soon L. Dormant but migratory tumour cells in desmoplastic stroma of invasive ductal carcinomas. Clin Exp Met 29:273-92 (2012) Raviraj V, Fok S, Zhao J, Chien H-Y, Lyons JG, Thompson EW, Soon L. Regulation of ROCK1 via Notch1 during breast cancer cell migration into dense matrices. BMC Cell Biol 13:12 (2012)
Hugo HJ, Kokkinos MI, Blick T, Ackland ML, Thompson EW, Newgreen DF. Defining the E-cadherin repressor interactome in epithelial-mesenchymal transition - The PMC42 model as a case study. Cells Tissues Organs 193: 23-40 (2011)
Thompson EW, Haviv I. The social aspects of EMT-MET plasticity. Nature Medicine "News and Views" 17(9): 1048-1049 (2011)
Prof Gregory Goodall is head of the Gene Regulation Laboratory at the Centre for Cancer Biology, Adelaide. His research revolves around the roles that microRNAs play in cancer metastasis. His group was among the first to construct and use microRNA microarrays, which in collaboration with the EMT group of Dr. Yeesim Khew-Goodall lead to the landmark discovery of a microRNA family that controls EMT, with important implications for tumour metastasis. Their report in Nature Cell Biol (2008) is the most highly cited of all papers on microRNAs in cancer. Prof Goodall has been a Postdoctoral Fellow of the Roche Institute of Molecular Biology, NJ, Research Fellow at Cornell University Medical School, NY and at the Friedrich Miescher Institute, Basel, Switzerland. He is currently chief investigator of the NBCF EMPathy Project Target Discovery theme, a chief investigator on 6 NHMRC grants and is an NHMRC senior research fellow. He serves on the editorial board of the journal Oncogene. He has served on the National Cancer Research Grants Specialty Committee 2001-2004, Cancer Council of SA Cancer Research Advisory Committee 2001-2003, Australian Cancer Research Foundation DNA Resources Committee, 2001-2004, NHMRC Grant Review Panels 2000, 2006-2008, 2011. He was chair of the organising committee for the 2011 Barossa Science Among the Vines and is chair of the program committee for the Combio 2012 conference. He is director of the ACRF SA Cancer Genome Research Facility.
Prof Goodall leads the Target Discovery stream of the EMPathy network. He and his group, along with Prof Thompson and various satellite investigators, will apply various discovery approaches to identify genes that affect EMT, invasion and metastasis, providing numerous candidates for assessment in the mechanism and pre-clinical themes for their potential as diagnostic or therapeutic targets.
Key Achievements and Awards
- Discovered further links between miR-200, ZEB transcription repressors and TGF-β in control of EMT.
- Used mouse cancer models to determine effects of miR-200 on cancer metastasis.
- Has developed genome wide methods for identifying microRNA targets in cancer cells.
Bracken CP, Li X, Wright JA, Lawrence D, Pillman KA, Salmanidis M, Anderson MA, Dredge BK, Gregory PA, Tsykin A, Neilsen C, Thomson DW, Bert AG, Leerberg JM, Yap AS, Jensen KB, Khew-Goodall Y, Goodall GJ. Genome-wide identification of miR-200 targets reveals a regulatory network controlling cell invasion. The EMBO Journal, 1-17, 2014.
Paterson EL, Kazenwadel J, Bert AG, Khew-Goodall Y, Ruszkiewicz A, Goodall GJ. Downregulation of the miRNA-200 family at the invasive front of colorectal cancers with degraded basement membrane indicates EMT is involved in cancer progression. Neoplasia 15:180-191, 2013
Thomson DW, Bracken CP, Szubert JM, Goodall GJ. On measuring miRNAs after transient transfection of mimics or antisense inhibitors. PlosOne 8:e55214, 2013.
Le TD, Liu L, Tsykin A, Goodall GJ, Liu B, Sun B_Y, and Li J. Inferring microRNA-mRNA causal regulatory relationships from expression data. Bioinformatics Jan 30, 2013
Lim YY, Wright JA, Attema JA, Gregory PA, Bert AG, Smith E, Thomas D, Drew PA, Khew-Goodall Y and Goodall GJ. Epigenetic modulation of the miR-200 family is associated with transition to a breast cancer stem cell-like state. J. Cell Sci. Accepted 27 February 2013.
Ahn Y-H, Gibbons DL, Chakravarti D, Rizvi ZF, Adams HP, Pertsemlidis A, Creighton CJ, Paterson EL, Gregory PA, Wright JA, Goodall GJ, Flores ER and Kurie JM. Zeb1 induces widespread changes in the miR transcriptome and controls biological processes other than EMT and stem-ness through repression of miR-34a . J. Clin. Invest. 122:3170-3183, 2012.
Neilsen PM, Noll JE, Mattiske S, Bracken CP, Gregory PA, Schulz RB, Lim SP, Kumar R, Suetani RJ, Goodall GJ and Callen DF. Mutant p53 drives invasion in breast tumors through up-regulation of miR-155. Oncogene Accepted 1 June 2012
Neilsen CT, Goodall GJ and Bracken CP. IsomiRs - the overlooked repertoire that contributes to the dynamic microRNAome Trends in Genetics 28: 544-549, 2012.
Price KJ, Tsykin A, Giles KM, Sladic RT, Epis MR, Ganss R, Goodall GJ, Leedman PJ. Matrigel Basement Membrane Matrix Influences Expression of microRNAs in Cancer Cell Lines. Biochem Biophys Res Commun. 427:343-348, 2012.
Khew-Goodall Y and Goodall GJ. A microRNA that limits metastatic colonisation and endothelial recruitment. EMBO J. 31: 786-787, 2012
Khew-Goodall Y and Goodall GJ. Stromal miR-320 keeps an oncogenic secretome in check. Nature Cell Biol. 14:124-125, 2012.
Terao M, Fratelli M, Kurosaki M, Zanetti A, Guarnaccia V, Paroni G, Tsykin A, Lupi M, Gianni M, Goodall GJ, Garattini E. Induction of miR-21 by Retinoic Acid in Estrogen Receptor-positive Breast Carcinoma Cells: Biological Correlates and Molecular Targets. J Biol Chem. 286:4027-42, 2011.
Yang Y, Ahn YH, Gibbons DL, Zang Y, Lin W, Thilaganthan N, Alvarez CA, Moreira DC, Creighton CJ, Gregory PA, Goodall GJ, Kurie JM, The Notch Ligand Jagged2 Promotes Tumor Cell EMT and Metastasis Through a GATA3/miR-200-dependent Pathway. J. Clin. Invest. 121:1373-1385, 2011.
Bracken CP, Szubert JM, Mercer TR, Dinger ME, Thomson DW, Mattick JS, Michael MZ, Goodall, GJ. Global analysis of the mammalian RNA degradome reveals widespread miRNA-dependent and miRNA-independent endonucleolytic cleavage. Nucl. Acids Res. 39:5658-5668, 2011.
Gregory PA, Bracken CP , Smith E, Bert AG, Wright JA, Roslan S, Morris M, Wyatt L, Lim YY, Farshid G, Lindeman GJ, Shannon MF, Drew PA, Khew-Goodall Y, Goodall GJ. A miR-200/ZEB/TGF-β signaling network regulates establishment and maintenance of epithelial-mesenchymal transition. Mol. Biol. Cell 22:1686-1698. 2011 (Journal Cover Feature)
McInnes N, Sadlon TJ, Brown CY, Pederson S, Beyer M, Schultze JL, McColl S, Goodall GJ, Barry SC. FOXP3 and FOXP3-regulated microRNAs suppress the expression of SATB1 in breast cancer cell lines. Oncogene doi: 10.1038 /onc.2011.293. [Epub ahead of print] 2011
Thomson DW, Bracken CP, Goodall GJ. Experimental strategies for microRNA target identification. Nucleic Acids Res. 39:6845-6853, 2011
Khew-Goodall Y, Goodall GJ. Myc-modulated miR-9 makes more metastases. Nature Cell Biol. 12:209-211, 2010
Winthrop Professor Christobel MB BS, FRCS (Gen), FRCS, FRACS is internationally recognised as one of Australia's most prominent research-orientated cancer surgeons. She has substantially contributed to many clinical aspects of breast cancer research including clinical trials of new treatments, psychosocial, translational and health services research and is active in several areas of surgical oncology cancer research, with a particular emphasis on breast cancer. Her career started as a surgical trainee in the UK and then Consultant Surgeon and Senior Lecturer at University College Hospitals in London, before moving to Australia in 2000 as a surgeon at Royal Perth Hospital and since 2002 as Professor of Surgical Oncology at the University of Western Australia.
She is responsible for conducting numerous clinical cancer projects and involved in multiple local, national and international clinical trials. She has performed research for >20 years evaluating the efficacy and utility of therapy for early breast cancer. Her research encompasses clinical trials, endocrine and exocrine aspects of breast cancer (including a population based study of endocrine therapy use and a large case control study of environmental risk factors for breast cancer), familial cancers, survivorship issues, minimally invasive diagnosis and therapy, and translational cancer research. Her interest in translational research has led her to set up, with Professor Wendy Erber at UWA, a translational cancer pathology laboratory and collaborate with Professor Robyn Anderson from the PeterMac who is setting up a national "warm autopsy" study of breast cancer metastases. She has strong interests in health services research and is Director of a Cancer Services Research Unit at UWA.
During the past 5 years she has been a Chief Investigator on 37 competitive grants with co-collaborators totalling over $17 million, published over 65 peer-reviewed journal articles 2 letters to the editor of peer reviewed journals, 2 book chapters, 4 invited publications, 1 report and 1 book. Based on her research there have been a number of advances in the management of breast cancer in Australia including the use of breast MRI to screen high risk women leading directly from her establishment of a national group establishing MRI as a screening tool for high risk women and the successful introduction of a Medicare Item number for this (of which she is currently submitting an extended application to the Department of Health and Ageing). Professor Saunders has another Medicare application underway to the Medical Scientific Advisory Committee (MSAC) for the emerging technology Intra-Operative Radiotherapy.
Professor Saunders is closely involved in strategic planning and management of cancer services and research in Australia as Council/Board member of Cancer Australia and previously the National Breast and Ovarian Cancer Centre, past Deputy Chair of the National Breast Cancer Foundation research advisory committee, author of WA Health Cancer Services Framework, first Acting Director of WA Cancer and Palliative Care Network, and voluntary work in cancer policy in the developing world. Advocacy work includes Board membership of Breast Cancer Network Australia and Cancer Council Australia and President of Cancer Council WA (2009-2013). Her work on the National Lead Clinicians Group has allowed her to put the cancer agenda on an even wider platform.
Professor Saunders contribution to the wider discipline include as a member of a number of external review panels including NHMRC; Cancer Council Australia; Cure Cancer Australia Foundation; National Breast Cancer Foundation; Netherlands Organisation for Health Research and Development, New Zealand Health Research Fund and an Australian Research Council assessor, reviewer or sub-editor for international and national journals. Her community engagement is demonstrated through her long standing work as Board member and President of the Cancer Council WA and Board member of the Breast Cancer Network Australia. She is a frequent lecturer on cancer to community groups and allied health professionals and her commitment to communicating with patients and the community is further demonstrated through ongoing dissemination of information in lay language such as: Breast Cancer: The Facts, published by Oxford University Press (2010), written to assist health professionals, and provide valuable information for patients, their families and friends, guiding readers informatively along the breast cancer journey. This book was 'highly commended' in the Popular Medicine category of the 2010 British Medical Association (BMA) Medical Book Competition. Lastly her commitment to teaching and mentoring of students and young researchers and surgeons is demonstrated through numerous avenues such as helping establish the UWA Student surgical Society, a mentoring programme for young women surgeons, as executive member of the RACS Women in Surgery Section, establishing the UWA Masters in Surgery programme, and mentoring countless young researchers and surgeons both formally through higher degrees and informally in research projects and in a pastoral care role.
Key Achievements and Awards
- Leading a successful, national application for the introduction of a Medicare item number for MRI as a screening tool for women at high risk for breast cancer - lead applicant to the Department of Health and Ageing
- 2nd Annual Kuwait Breast Diseases & Oncoplastic Reconstructive Surgery Conference Certificate of Appreciation (2010)
- NBCF Patron’s Award for achievement in breast cancer research (2010)
Certificate of Outstanding Service Royal Australasian College of Surgeons (2011)
Professor Saunders is a co-author of the book Breast Cancer: The Facts, which was short listed for the BMA Book of the Year in 2010. A photograph taken for the book won an international competition in the Lancet and appeared as a Highlight in Volume 378 (combined issues 17/24/31), December 2011.
A publication highlight has been a co-authored article in the Lancet in 2010 (Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial) which received the University of Western Australia’s Vice Chancellor’s Incentive Award ($10,000) for High Quality Research in 2010. This article also resulted in Professor Saunders being named as one of UWA’s Highly Cited Researchers & Authors of Western Australia’s 2010 Highly Cited Papers of the last decade list produced by Thomson Reuters ISI, and one of 14 medicine papers from UWA (March 2012).
A/Prof Robin Anderson is Head of the Metastasis Research Laboratory at the Peter MacCallum Cancer Centre and holds an honorary appointment of Principal Fellow in the Sir Peter MacCallum Department of Oncology at The University of Melbourne. Commencing in 2009, she was awarded a career fellowship from the NBCF for continued research in breast cancer metastasis, for which she has had a longstanding interest. Since 1997 her group has developed breast cancer metastasis models, including the only model that mimics the clinical behaviour of breast cancer, with reliable and substantial metastasis to bone. This research has been funded by the US Department of Defense, The Susan G. Komen for the Cure (USA), the NIH/NCI, the NHMRC, The Cancer Council of Victoria, AICR, Cancer Australia and the NBCF.
Expression profiling of tumours with varying metastatic potential within the models has yielded some novel potential metastasis regulating genes that are the subject of on-going studies. She has also developed an interest in tumour/stromal interactions, again using these clinically relevant metastasis models. Her research is well recognised in USA and Europe, as evidenced by many invitations to speak at national and overseas conferences. She reviews for many journals and funding agencies, has been a Grant Review Panel member for the NHMRC and the NBCF, is the Editor-in-Chief of Clinical & Experimental Metastasis, an Editorial Board Member of Cell Stress & Chaperones, a member of the Board of Directors of the International Metastasis Research Society, a member of the Scientific Committee of the Victorian Breast Cancer Research Consortium and on the organising committees of several conferences, including the program committee for the AACR Annual Meeting in Washington, DC in April 2010 and the 14th International congress of the Metastasis research Society in Brisbane in 2012.
Associate Professor Anderson has mentored over 25 honours and PhD students and several postdoctoral fellows who have established or are establishing independent careers in cancer research. She has published 100 original research and review articles, the more recent ones focusing on her metastasis research.
Key Achievements and Awards
- NBCF Infrastructure Grant, "NBCF Repository of Primary tumours and Metastases from Breast Cancer patients" (2014)
- The development of a therapy that targets established metastases (Yu Miao et al, 2013)
- The demonstration that the oncogene c-Myb is required for growth of both mouse and human breast cancer cells and tumours and is required for onset of mammary tumours in transgenic mouse models (Yu Miao et al., 2011)
- The demonstration that stromally derived caveolin-1 in the tumour microenvironment is a strong, independent prognostic factor in breast cancer. Loss of stromal caveolin-1 correlates with poor prognosis (Sloan et al., 2009)
- The demonstration that BMP4 is a powerful suppressor of metastasis in mouse models and low BMP4 expression correlates with poor outcome in patients with ER positive breast cancer (Eckhardt et al., manuscript in preparation)
Swierczak, A, Cook, AD, Lenzo, JC, Restall, CM, Doherty, J, Anderson, RL* and Hamilton, JA* (2014) The promotion of breast cancer metastasis caused by inhibition of CSF-1R/CSF-1 signaling is blocked by targeting the G-CSF receptor. Cancer Immunology Research (On-line First, April 29, 2014).
Cao, Y, Slaney, CY, Bidwell, BN, Parker, BS, Johnstone, CJ, Rautela, J, Eckhardt, BL* and Anderson, RL* (2014). Bone morphogenetic protein-4 inhibits breast cancer metastasis by blocking myeloid derived suppressor cell activity. Cancer Research (accepted, June 2014).
Martin, OA, Anderson, RL, Russell, PA, Cox, RA, Ivashkevich, A, Swierczak, A, Doherty, J, Jacobs, DHM, Smith, J, Siva, S, Daly, PE, Ball, DL, Martin, RF, MacManus, MP (2014). Mobilisation of viable tumor cells into the circulation during radiation therapy. International Journal of Radiation Oncology, Biology, Physics 88: 395-403.
Denoyer, D, Kusuma, N, Burrows, A, Ling, X, Jupp, L, Anderson, RL and Pouliot, N. (2014). Bone-derived soluble factors and laminin-511 cooperate to promote migration, invasion and survival of bone-metastatic breast tumor cells. Growth Factors (accepted).
Li, R, Doherty, J, Antonipillai, J, Chen, S, Devlin, M, Visser, K, Baell, J, Street, I, Anderson, RL* and Bernard, O* (2013). LIM kinase inhibition reduces breast cancer growth and invasiveness but systemic inhibition does not reduce metastasis in mice. Clinical & Experimental Metastasis 30: 483-495. *joint senior authors.
Redvers, R and Anderson, RL (2013). Long Non-Coding RNA: Agent Provacateur in Breast Cancer Metastasis. In Metastatic Cancer: Clinical and Biological Perspectives. Editor R. Jandial. Landes Press, pp. 180-199.
Cuello-Carrion, FD, Cayado-Gutierrez, N, Natoli, AL, Restall, C, Anderson, RL, Nadin, S, Alvarez-Olmedo, D, Castro, GN, Gago, FE, Fanelli, MA and Ciocca, DR (2013). In MMTV-Her-2/neu transgenic mammary tumors the absence of caveolin-1 (-/-) alters PTEN and NHERF1 but not b-catenin expression. Cell Stress & Chaperones 18:559-567.
Purdom, E, Restall, C, Busuttil, RA, Schluter, H, Boussioutas, A, Thompson, EW, Anderson, RL, Speed, TP and Haviv, I (2013). Determining epithelial contribution to in vivo mesenchymal tumour expression signature using species-specific microarray profiling analysis of xenografts. Genetics Research 95: 14-29.
Yu Miao, R, Eckhardt, BL, Cao, Y, Pasqualini, R, Argani, P, Arap, W, Ramsay, R* and Anderson, RL* (2013). Inhibition of Established Metastases by Targeted Drug Delivery via Cell Surface Associated GRP78. Clinical Cancer Research 19: 2107-2116. *joint senior authors
Fernandez-Rojo, MA, Gongora, M, Fitzsimmons, RL, Martel, N, Martin, SD, Nixon, SJ, Brooks, AJ, Ikonomopoulou, MP, Martin, S, Lo, HP, Myers, SA, Restall, C, Ferguson, C, Pilch, PF, McGee, SL, Anderson, RL, Waters, MJ, Hancock, JF, Grimmond, SM, Muscat, GEO and Parton, RG. (2013) Caveolin-1 Is Necessary for Hepatic Oxidative Lipid Metabolism: Evidence for Crosstalk between Caveolin-1 and Bile Acid Signaling. Cell Reports 4: 1-10.
Li, X, Roslan, S, Johnstone, CN, Wright, JA, Bracken, CP, Anderson, MJ, Bert, AG, Selth, LA, Anderson, RL, Goodall, GJ, Gregory, PA and Khew-Goodall, Y. (2013). MiR-200 can repress breast cancer metastasis through ZEB1-independent, but moesin-dependent pathways. Oncogene (in press).
Prof Alpha Yap is a Group Leader and Head of the Division of Molecular Cell Biology at the Institute for Molecular Bioscience, The University of Queensland and a Research Fellow of the NHMRC. After clinical training in Internal Medicine/Endocrinology and graduate studies in Cell Physiology, he undertook post-doctoral research with Barry Gumbiner at Memorial Sloan-Kettering Cancer Center before returning to Australia to establish his independent research group. His laboratory studies the cellular mechanisms responsible for cadherin-dependent morphogenesis, notably the signalling pathways that support functional and molecular cooperation between cadherin cell adhesion and the cytoskeleton. His group is funded by the National Health and Medical Research Council of Australia and Australian Research Council. Alpha Yap was President of the Australia and New Zealand Society for Cell and Developmental Biology from 2006-2008. He serves on the editorial boards of several journals, including Molecular Biology of the Cell and Current Biology.
Within the EMPathy network he leads the Mechanisms stream. Here, he and his group will apply their expertise in cell biology to analyse how target molecules discovered by the consortium affect tumor cell-cell interactions, migration and patterning.
Key Achievements and Awards
- Vice-Chair, Gordon Research Conference on Signaling by Adhesion Receptors (2014)
- Discovery of actin regulators that control junctional contractility and oncogenic cell extrusion (Kovacs et al., 2011; Wu, Gomez et al., 2014)
- Principal Research Fellow of the National Health and Medical Research Council of Australia (2013)
- President's Medal of the Australia and New Zealand Society for Cell and Developmental Biology (2013)
- Discovery of pathways that regulate Rho signaling at cell-cell junctions (Ratheesh, Gomez et al., 2012)
- Chair, Gordon Research Conference on Cell Contact & Adhesion (2011)
Wu, S.K., G.A. Gomez, M. Michael, S. Verma, H.L. Cox, J.G. Lefevre, R.G. Parton, N.A. Hamilton, Z. Neufeld and A.S. Yap (2014). Cortical F-actin stabilization generates apical-lateral patterns of junctional contractility that integrate cells into epithelia. Nature Cell Biology 16, 167-178. (Subject of N&V in Nature Cell Biology 16, 127-129)
Han, S.P, Y. Gambin, G.A. Gomez, S. Verma, N. Giles, M. Michael, S.K. Wu, Z. Guo, W. Johnston, E. Sierecki, R.G. Parton, K. Alexandrov and A.S. Yap (2014). Cortactin scaffolds Arp2/3 and WAVE2 at the epithelial zonula adherens. J. Biol. Chem. 289, 7764-7775 (Chosen as JBC Paper of the Week and Cover image for issue)
Leerberg, J.M., G.A. Gomez, Suzie Verma, E.J. Moussa, S.K. Wu, R. Priya, B.D. Hoffman, C. Grasshof, M.A. Schwartz and A.S. Yap (2014). Tension-sensitive actin assembly supports contractility at the epithelial zonula adherens. Current Biology (In press)
Ratheesh, A., G.A. Gomez, R. Priya, S. Verma, E.M. Kovacs, K. Jiang, N.H. Brown, A. Akhmanova, S.J. Stehbens, and A.S. Yap (2012). Centralspindlin and a-catenin regulate Rho signaling at the epithelial zonula adherens. Nature Cell Biology 14, 818-828
Kovacs, E.M., S. Verma, R.G. Ali, A. Ratheesh, N.A. Hamilton, A. Akhmanova and A.S. Yap (2011). N-WASP regulates the epithelial junctional cytoskeleton by a non-canonical post-nucleation mechanism. Nature Cell Biology 13, 934-943.
Mangold, S., S.K. Wu, S.J. Norwood, B.M. Collins, N.A. Hamilton, P. Thorn and A.S. Yap (2011). Hepatocyte growth factor acutely perturbs actin filament anchorage at the epithelial zonula adherens. Current Biology 21: 503-507.
Dr Ian Street has over 19 years experience working in the field of drug discovery, within the international pharmaceutical industry, the Australian biotechnology companies AMRAD and Bionomics, and more recently in academia at the Walter and Eliza Hall Institute (WEHI), where in 2001 he established and ran the very successful Centre for High Throughput Chemical Screening, one of the world’s first academic high throughput screening groups. Before working at WEHI, Dr Street spent 11 years in the pharmaceutical and biotech industries. During his career he has worked with some of the world’s leading pharmaceutical
companies including, Merck, Aventis, Chiron, GSK, Genentech and Abbott; a body of work which has contributed to compounds entering development, clinical trials and the market. Dr Street now brings these valuable industry links, R&D expertise, and business acumen to academic drug discovery projects in his current roles as Head of the WEHI HTCS Facility and Chief Scientific Officer of the recently established Cancer Therapeutics CRC (CTx). Dr Street now directs CTx’s R&D program and project portfolio. He also manages the CRC’s technology relationship with partners and stakeholders and is responsible for the Portfolio Management Group, CTx’s prime forum for evaluating and selecting new projects and monitoring the performance of projects in the pipeline.http://www.wehi.edu.au/Key Achievements and Awards
- Two compounds that have entered clinical trials in the past 3 years
- The Cancer Therapeutics CRC achieving its first major milestone by nominating a licensing candidate
- Four Patent Applications (3 licensed for commercialization and development)
Recent PublicationsSleebs, B.E., P.E. Czabotar, W.J. Fairbrother, W.D. Fairlie, J.A. Flygare, D.C.S. Huang, W.J.A. Kersten, M.F.T. Koehler, G. Lessene, K. Lowes, J.P. Parisot, B.J. Smith, M.L. Smith, A.J. Souers, I.P. Street, H. Yang, J.B. Baell. Quinazoline Sulfonamides as Dual Binders of the Proteins B-Cell Lymphoma 2 and B-Cell Lymphoma Extra Long with Potent Proapoptotic Cell-Based Activity. J. Medicinal Chem. 2011 54(6):1914-1926.
Patterson, S., M.S. Alphey, D.C. Jones, E.J. Shanks, I.P. Street, J.A. Frearson, P.G. Wyatt, I.H. Gilbert, A.H. Fairlamb. Dihydroquinazolines as a Novel Class of Trypanosoma brucei Trypanothione Reductase Inhibitors: Discovery, Synthesis and Characterization of their Binding Mode by Protein Crystallography. J. Medicinal Chem. 2011 13; 54(19):6514-6530.
Sleebs, B.E., G. Nikolakopoulos, I.P. Street, H. Falk, J.B. Baell.Identification of 5,6-substituted 4-aminothieno[2,3-d]pyrimidines as LIMK1 inhibitors. Bioorganic & Medicinal Chemistry Letters 2011 21(19):5992-5994.
Falk, H., T. Connor, H. Yang, K.J. Loft, R.N. Surjadi, J.D. Bentley, M.K. Hattarki, O. Dolezal, J.M. Murphy, B.J. Monahan, T.S. Peat, T. Thomas, J.B. Baell, J.P. Parisot, I.P. Street. An Efficient High-Throughput Screening Method for MYST Family Acetyltransferases, a New Class of Epigenetic Drug Targets. J. Biomolecular Screening 2011 16(10):1196-1205.Holloway, G.A., J.P. Parisot, P.M. Novello, K.G. Watson, T. Armstrong, R.C. Thompson, I.P. Street, J.B. Baell. Discovery of novel and potent benzhydryl-tropane trypanocides highly selective for Trypanosoma cruzi. Bioorg Med Chem Lett. 2010 20(6):1816-1818.
Holloway, G.A., W.N. Charman, A.H. Fairlamb, R. Brun, M. Kaiser, E. Kostewicz, P.M. Novello, J.P. Parisot, J. Richardson, I.P. Street, K.G. Watson, J.B. Baell. Trypanothione Reductase High-Throughput Screening Campaign Identifies Novel Classes of Inhibitors with Antiparasitic Activity. Antimicrob. Agents Chemother. 2009 53(7):2824-2833.
A/Prof Alex Dobrovic is head of the Molecular Pathology Research and Development Lab at the Peter MacCallum Cancer Centre. He is expert in mutation, methylation and expression analysis of clinical samples and has published extensively in this area. He has designed and tested the assays to be used in the EMPathy BCN grant and will supervise their performance and interpretation.
Associate Professor Alexander Dobrovic has a PhD in Genetics and has since been an active researcher in cancer molecular genetics and pathology. He has a focus on personalized medicine including developing clinically relevant innovative diagnostic methodologies. This includes tests for detection of KRAS, BRAF and TP53 mutations that have entered routine diagnostics. He is also developing protocol for detecting cancer using the plasma fraction of blood. These interests will be continued by overseeing diagnostic development in the EMPathy BCN program.
His group has worked solidly on genetic and epigenetic determinants of response to therapy and has developed important collaborations with Australian and international researchers. A major research interest is the desire to transform chemotherapy into targeted therapy by identifying molecular targets using high dynamic range gene expression and DNA methylation analysis. Another major research interest is in the emerging field of examining the role of epigenetics in cancer predisposition, in particular the constitutional mosaic methylation of hereditary cancer and other recessive cancer genes. This requires the development of methods of DNA methylation analysis that are both accurate and sensitive. A new focus is on understanding plasticity in cancer and its role in drug resistance. This may bear a strong relationship to the epithelial mesenchymal plasticity that is the focus of this EMPathy consortium.
Key Achievements and Awards
- Demonstrating a novel mechanism of breast cancer predisposition (Wong et al., 2011)
- New understanding of complex methylation patterns (Mikeska et al., 2010; Candiloro et al., 2011)
Development of methodologies for more accurate detection of mutations in clinical samples (Do et al., 2009)
Candiloro IL, Mikeska T, Dobrovic A. Assessing combined methylation-sensitive high resolution melting and pyrosequencing for the analysis of heterogeneous DNA methylation. Epigenetics 2011 6:501-508.
Hondow HL, Fox SB, Mitchell G, Scott RJ, Beshay V, kConFab investigators, Dobrovic A. A high-throughput protocol for mutation scanning of the BRCA1 and BRCA2 genes. BMC Cancer 2011 11:265.
Ee Ming Wong, Southey MC, Fox SB, Brown MA, Dowty J, Jenkins Mark A, Giles GG, Hopper JL, Dobrovic A. Constitutional methylation of the BRCA1 promoter is specifically associated with BRCA1-like pathology in early-onset breast cancer. Cancer Prev. Res. 2011 4:23-33.
Mikeska T, Candiloro I, Dobrovic A. The methodological implications of heterogeneous DNA methylation for the use of methylation as a biomarker. Epigenomics 2010 2:561-73
Takano EA, Mikeska T, Dobrovic A, Byrne DJ, Fox SB. A multiplex endpoint RT-PCR assay for quality assessment of RNA extracted from formalin-fixed paraffin-embedded tissues. BMC Biotechnol. 2010 10:89.Dobrovic A, Kristensen LS. DNA methylation, epimutations and cancer predisposition. Int J Biochem Cell Biol. 2009 41:34-39.
Do H, Dobrovic A. Limited copy number - high resolution melting (LCN-HRM) enables the detection and identification by sequencing of low level mutations in cancer biopsies. Mol Cancer 2009 8:82.
Candiloro IL, Dobrovic A. Detection of MGMT promoter methylation in normal individuals is strongly associated with the T allele of the rs16906252 MGMT promoter single nucleotide polymorphism. Cancer Prev Res. 2009 2:862-7.
Whitehall V, Tran K, Umapathy A, Grieu F, Hewitt C, Evans TJ, Ismail T, Li WQ, Collins P, Ravetto P, Leggett B, Salto-Tellez M, Soong R, Fox S, Scott RJ, Dobrovic A, Iacopetta B. A multicenter blinded study to evaluate KRAS mutation testing methodologies in the clinical setting. J Mol Diagn. 2009 11: 543-52Alsop K, Fereday S, Meldrum C, Bhatt N, DeFazio A, Emmanuel C, George J, Dobrovic A, Birrer MJ, Webb PM, The Australian Ovarian Cancer Study Group, Stewart C, Friedlander M, Fox SB, Bowtell D, Mitchell G. BRCA mutation frequency and patterns of treatment response in BRCA mutation positive women with ovarian cancer. J. Clin Oncol (accepted)
Mikeska T, Bock C, Dobrovic A. DNA methylation biomarkers in cancer: progress towards clinical implementation. Expert Review of Molecular Diagnostics (accepted)
Kristensen LS, Raynor M, Candiloro IL, Dobrovic A. Methylation profiling of peripheral blood mononuclear DNA from normal individuals reveals mosaic promoter methylation of cancer associated genes. Oncotarget (accepted)
Dr. Anthony Dowling completed Medical Oncology training with a fellowship at Princess Margaret Hospital in Toronto, Canada, working under Professor Ian Tannock. Whilst there he completed a certificate in Clinical Epidemiology at the University of Toronto. Since 1999 Dr Dowling has had a full time appointment as a Medical Oncologist at St Vincent’s Hospital, Melbourne. He also is Visiting Medical Officer for several city private hospitals; St Vincents and Mercy Private, Freemasons Hospital, Epworth Eastern, Werribee Mercy Hospital and the regional centre Goulburn Valley Health.
Dr Dowling has a special interest in breast and urogenital cancers, and neuro-oncological tumours. He has been actively involved in clinical trials throughout his career and currently is either the principal or associate investigator in many clinical trials. Through the Clinical Drug Trial Subcommittee of the Human Research Ethics Committee and the Human Research Ethics Committee – Drugs of St. Vincent’s Hospital (1999-2005), he has had an active role critiquing drug trials that have been submitted to St. Vincent’s Hospital.
Dr Dowling is involved in many breast cancer studies, including neo-adjuvant studies looking at molecular markers and correlates with chemo-responsiveness, adjuvant and metastatic studies. He works with a number of colleagues that have access to a large number of breast cancer patients, who are potential participants in clinical trials. Since 1999 Dr Dowling has also been a lecturer at The University of Melbourne, giving lectures to medical students. He is also involved in resident teaching as well as postgraduate training of physician trainees with short and long case preparation, trial exams and mentoring. He has been an examiner for the clinical physician exam since 2003. He is also a writer and editor for several modules of the distant-learning program for registered nurses with The Cancer Council Victoria and Latrobe University, and the Patient Information Booklets distributed by The Cancer Council Victoria. Since 2007, Dr Dowling is the Medical Oncology representative from Australia and New Zealand on the Written Examination Committee – Adult Medicine for The Royal Australasian College of Physicians, which write the exam questions for the annual FRACP written examination. He is a regular speaker at cancer support groups, to volunteers of the Cancer Council Victoria and a participant in ‘Cancer Call-In’ sessions.
In 2011 he was the recipient of a Victorian Travelling Fellowship from the Victorian Quality Council. He undertook a three months sabbatical on the management of high grade gliomas at Memorial Sloan Kettering Cancer Center in New York, New York.
In the EMPathy BCN program he co-ordinates the Clinical Trial Theme, is involved in the Clinical Validation Theme and in the recruitment of patients with operable breast cancer to sample blood and bone marrow for the isolation and characterization of circulating and disseminated tumour cells.
Key Achievements and Awards
- Recipient of a Victorian Travelling Fellowship from the Victorian Quality Council (2011)
Ng SL, Burns WI, Snyder RD, Newnham GM, McLachlan S-A, Liew D, Dowling AJ. A retrospective cohort study of metastatic colorectal cancer patients treated with oxaliplatin-based chemotherapy, with an exploratory analysis of changing serum carcinoembryonic antigen levels. Asia-Pacific J. Clin. Oncology (2012).Ananda S, Nowak AK, Cher L, Dowling A, Brown C, Simes J, Rosenthal MA, Cooperative Trials Group for Neuro-Oncology (COGNO). Phase II trial of temozolomide and pegylated liposomal doxorubicin in the treatment of patients with glioblastoma multiforme following concurrent radiotherapy and chemotherapy. J. Clin. Neuroscience 18:1444-1448 (2011).
Gan HK, Rosenthal MA, Dowling A, Kalnins R, Algar E, Benson A, Woods AM, Cher L. A phase II trial of primary temozolomide in patients with grade III oligodendroglial brain tumours. Neuro Oncology 12:500-507 (2010).