Cancer Signalling Research Laboratory

  • Dr Hong-Jian Zhu
    T: +61 3 8344 3025
    E: hongjian@unimelb.edu.au
    Location: 527, Clinical Sciences Building,
    Royal Melbourne Hospital

Research Overview

Dr Hong-Jian Zhu’s laboratory focuses on discovering the molecular signalling pathways regulating cancer cell development, from initiation and growth to dissemination, circulation and metastatic seeding.

Targeted therapy is one of the most outstanding successes in cancer treatments today and it is continuing as a major strategic direction for large pharmaceutical companies around the word. It’s typified by the development of these “silver/magic bullets” such as Imatinib, also known as Gleevec and STI571, for treatment of chronic myeloid leukemia (CML); Vemurafenib (PLX4032) for late-stage melanoma and Crizotinib (Xalkori) for non-small cell lung carcinoma (NSCLC). Fundamental to all these successes are the discoveries of Bcr-abl, B-Raf(V600A), and Eml4-Alk as the true molecular causes of these cancers respectively.

In contrast, there have been many not so successful “miss-targeted bullets” for example the underwhelming results of 20+ phase I, II, III clinical trials targeting TGF-β signalling for treatment of various types of cancers. While it is clear that TGF-β signalling is a major molecular driver for cancer progression, particularly invasion and metastasis, it is in the context of signalling pathway of ligand-receptor-Smad-targeted gene activation. What we have now discovered is that the bioactive microvesicle exosomes are the key regulator of TGF-β signalling, bypassing the traditional ligand-receptor as the signalling initiators. More strikingly, the conventional ligand targeting therapies have little effect on the exosomal TGF-β, directly and clearly explaining the reasons for not so successful outcomes of clinical trials.

The lab currently are geared towards establishing a new paradigm whereby exosomes are the initiator and amplifier of TGF-β signalling that in turn is the true molecular cause of cancer invasion and metastasis. The research projects covers from basic understanding of how at molecular level exosomes delivers tumourigenic TGF-β signalling, particularly in the context of tumour microenvironment to new therapeutic strategy and therapies for treatment of various type human cancers, i.e. breast, brain, colon and skin cancers.

In addition, we are also developing a new generation of anti-TGF-β therapy with much improved delivery together with cancer vaccination targeting TGF-β signalling's role in immuno-supression. The focuses of latter are on melanoma and breast cancers.

Staff

  • Dr Hong-Jian Zhu, PhD, Head
  • Ms Josie Iaria, Research Assistant
  • Ms Jingyi Sheng, PhD student
  • Ms Linda Yanghong Wang, PhD student
  • Sarah Broome, Honours Student
  • Jennifer Wang, Honours Student
  • Mark Jenkins, Honours Student

Collaborators

  • Prof Pater ten Dijke, Leiden University , The Netherlands
  • Prof Richard Simpson, La Trobe University
  • Prof Tony Burgess, WEHI
  • Prof Weisan Chen, La Trobe University
  • A/Prof Oliver Sieber, WEHI
  • Prof Long Zhang, Zhejiang University, China
  • Prof Huiyao Lan, Hong Kong Chinese University, China
  • Prof Zihe Rao, Tsinghua University, China
  • Dr Rommel Mathias, Monash University

Funding

  • Royal Melbourne Hospital Neurosciences Foundation project grant, Biology of brain tumours; NH&MRC Project Grant, No 628727, Integrating Wnt-APC pathway with TGF-β Signaling in Colon Cancer;
  • NH&MRC Project Grant, No. 433618, Loss of cytostatic regulation by TGF-β during EGFR-driven tumor developmen;
  • NH&MRC Project Grant, No. 433619, Expansion of TGF-β-Smad signaling network and intrinsic epithelial-mesenchymal-endothelial transition;
  • NH&MRC Project Grant, No. 400156, How does abnormal regulation of Src-family kinase cause cancer;
  • NH&MRC Project Grant, No. 331005, The Role of TGF-β Signaling in Suppression of Stat3-mediated Tumorigenesis;
  • Cancer Council Victoria Project Grant 2005-2007, Regulation of PTEN Activity and Subcellular localization;
  • NH&MRC Project Grant, No. 280913, Differential Cooperation of MAPKs with TGF-β Signaling in Epithelial-Mesenchymal Transition;
  • NH&MRC Project Grant, No.164812, pecificity of Smad Proteins in Transforming Growth Factor-β Signaling.

Research Publications

Rong Xu, David Greening, Hong Jian Zhu, Nobuhiro Takahashi and Richard Simpson, Extracellular vesicle isolation and characterization: towards clinical application, Journal of Clinical Investigation, 2016 (Accepted in Feb) (IF=13.6)

Rodney B. Luwor, Dulani Hakmana, Josephine Iaria, Thao V Nheu, Richard J Simpson and Hong-Jian Zhu, Single Live Cell TGF-β Signalling Imaging: Breast Cancer Cell Motility and Migration is Driven by Sub-populations of Cells with Dynamic TGF-β-Smad3 Activity, Molecular Cancer, 2015, 14:50, 1-8, DOI 10.1186/s12943-015-0309-1, (IF=5.4)

Rong Xu, David Greening, Hong Jian Zhu, Nobuhiro Takahashi and Richard Simpson, Extracellular vesicle isolation and characterization: towards clinical application, Journal of Clinical Investigation, 2016 (Accepted in Feb) (IF=13.6)

Rodney B. Luwor, Dulani Hakmana, Josephine Iaria, Thao V Nheu, Richard J Simpson and Hong-Jian Zhu, Single Live Cell TGF-β Signalling Imaging: Breast Cancer Cell Motility and Migration is Driven by Sub-populations of Cells with Dynamic TGF-β-Smad3 Activity, Molecular Cancer, 2015, 14:50, 1-8, DOI 10.1186/s12943-015-0309-1, (IF=5.4)

Sheng Liu, Thao Nheu, Rodney Luwor, Sandra E Nicholson and Hong-Jian Zhu, SPSB1, a Novel Negative Regulator of the TGF-β Signaling Pathway Targeting the Type II Receptor, J. Biol. Chem. 2015 290, 17894-17908, DOI:10.1074/jbc.M114.607184 (IF=4.6)

Fangfang Zhou, Yvette Drabsch, Tim Dekker, Amaya Garcia de Vinuesa, Yihao Li, Lukas JAC Hawinkels, Kelly-Ann Sheppard, Marie-Jose Goumans, Rodney Luwor, Carlie de Vries, Wilma W.E. Mesker, Rob Tollenaar, Peter Devilee, Chris Lu, Hongjian Zhu, Long Zhang, and Peter Ten Dijke, Nuclear receptor NR4A1 promotes breast cancer invasion and metastasis by activating TGF-β signaling, Nature Communications, 5:3388. 1-13 DOI:10.1038/ncomms4388, 2014 (IF=10.7)

Rodney B. Luwor, Behzad Baradaran, Lauren E. Taylor, Josephine Iaria, Thao V. Nheu, Naeem Amiry, Christopher M. Hovens, Bo Wang, Andrew H Kaye and Hong-Jian Zhu Targeting Stat3 and Smad7 to Restore TGF-β Cytostatic Regulation of Tumor Cells In Intro and In Vivo, Oncogene, 32, 2433-41, 2013 (IF=8.6)

Yuan-Shou Chen, Rommel A. Mathias, Suresh Mathivanan, Eugene A. Kapp, Robert L. Moritz, Hong-Jian Zhu* and Richard J. Simpson*, Proteomic profiling of MDCK plasma membranes reveals Wnt-5a involvement during oncogenic H-Ras/TGF-β-mediated epithelial-mesenchymal transition, Mol. Cell. Proteomics, 10:10.1074/mcp.M110.001131, 1–15, 2011  (IF=7.25)

Rodney B. Luwor, Bo Wang, Thao V. Nheu, Josephine Iaria, Evelyn Tsantikos, Margaret L. Hibbs, Oliver M. Sieber and Hong-Jian Zhu New Reagents for Improved in vitro and in vivo Examination of TGF-β Signalling, Growth Factors, 29, 211-218, 2011 (IF=3.1)

Jenkins BJ, Grail D, Nheu T, Najdovska M, Wang B, Waring P, Inglese M, McLoughlin RM, Jones SA, Topley N, Baumann H, Judd LM, Giraud AS, Boussioutas A, Zhu H-J* and Ernst M*. Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-β signaling Nat. Medicine 11, 845-52/DOI: 10.1038/Nm1282 2005  (IF=28.1)

Stenvers KL, Tursky ML, Kountouri N, Amatayakul-Chantler S, Grail D, Small C, Weinberg RA, Sizeland AM and Zhu H-J. Heart and Liver Defects and Reduced Transforming Growth Factor-β2 Sensitivity in Transforming Growth Factor-β Type III Receptor-Deficient Embryos. Mol. Cell. Biol. 23, 4371-4385, 2003. (IF=5)

Garrett TPJ, McKern NM, Lou M, Elleman TC, Adams TE, Lovrecz GO, Zhu H-J, Walker F, Hoyne PA, Jorissen RN, Nice EC, Burgess AW and Ward CW. Crystal Structure of a Truncated Epidermal Growth Factor Receptor Extracellular Domain Bound to Transforming Growth Factor-α. Cell 110: 763-773, 2002  (IF=33.1)

Research Projects

This Research Group doesn't currently have any projects



Faculty Research Themes

Cancer

School Research Themes

Cancer in Medicine



Key Contact

For further information about this research, please contact Dr Hong-Jian Zhu

Department / Centre

Surgery

Unit / Centre

Cancer Signalling Research Laboratory