Cancer Signalling Research Laboratory

Researcher

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 Outcomes

  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 (* corresponding author)
  2. Xiao Y, Yeong Chit Chia J, Gajewski JE, Sio Seng Lio D, Mulhern TD, Zhu H-J, Nandurkar H, Cheng H-C. PTEN catalysis of phospholipid dephosphorylation reaction follows a two-step mechanism in which the conserved aspartate-92 does not function as the general acid - Mechanistic analysis of a familial Cowden disease-associated PTEN mutation Cell. Signal. 19, 1434-45, 2007
  3. Hirokawa Y, Levitzki A, Lessene G, Baell J, Xiao Y, Zhu H, Maruta H. Signal therapy of human pancreatic cancer and NF1-deficient breast cancer xenograft in mice by a combination of PP1 and GL-2003, anti-PAK1 drugs (Tyr-kinase inhibitors). Cancer Lett. 245, 242-51, 2007
  4. Ji H, Moritz RL, Kim Y-S, Zhu H-J, Simpson RJ. Analysis of Ras-induced oncogenic transformation of NIH-3T3 cells using differentialdisplay. Electrophoresis 28, 1997-2008, 2007
  5. Gajewski JE, Bird MJ, Crowhurst MO, Sio-Seng Lio D, Liu J, Wettenhall RE, Zhu HJ, Cheng HC. Expression, generation, and purification of unphosphorylated and phospho-Ser-380/Thr-382/Thr-383 form of recombinant PTEN phosphatise. Protein Expr. Purif. 55, 334-42, 2007
  6. Luwor RB, Kaye AH, Zhu HJ. Transforming growth factor-beta (TGF-beta) and brain tumours. J Clin Neurosci. 15, 845-55, 2008.
  7. Ji H, Erfani N, Tauro BJ, Kapp EA, Zhu HJ, Moritz RL, Lim JW, Simpson RJ. Difference gel electrophoresis analysis of Ras-transformed fibroblast cell-derived exosomes. Electrophoresis. 29, 2660-71, 2008.
  8. Mathias RA, Wang B, Ji H, K Eugene, Moritz R, Zhu H-J, Simpson R. Secretome-Based Proteomic Profiling of Ras-Transformed MDCK Cells Reveals Extracellular Modulators of Epithelial-Mesenchymal Transition. J Proteome Res. 8, 2827-2837, 2009.
  9. Tsantikos E, Quilici C, Harder KW, Wang B, Zhu H-J, Anderson GP, Tarlinton DM and Hibbs ML. Perturbation of the CD4 T cell compartment and expansion of regulatory T cells in autoimmune-prone Lyn-deficient mice. J Immunology 183, 2484-2494, 2009.
  10. Mathias RA, Chen YS, Wang B, Ji H, Kapp EA, Moritz RL, Zhu H-J, Simpson RJ  Extracellular Remodelling During Oncogenic Ras-Induced Epithelial-Mesenchymal Transition Facilitates MDCK Cell Migration. J Proteome Res. 9, 1007-1019, 2010
  11. Chia JY, Gajewski JE, Xiao Y, Zhu HJ, Cheng HC Unique biochemical properties of the protein tyrosine phosphatase activity of PTEN-demonstration of different active site structural requirements for phosphopeptide and phospholipid phosphatase activities of PTEN. Biochim Biophys Acta. 1804, 1785-95, 2010
  12. 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 (* corresponding author)
  13. Yugang Tu, Tieqiao Wu, Aozhi Dai, Yen Pham, Phyllis Chew, Judy B de Haan, Yu Wang, Ban-Hock Toh, Hongjian Zhu, Zemin Cao, Mark E Cooper and Zhonglin, Cell division autoantigen 1 enhances signaling and the profibrotic effects of transforming growth factor-β in diabetic nephropathy, Kidney Int., 79 (2), 199-209, 2011
  14. Mathias RA, Chen YS, Goode RJ, Kapp EA, Mathivanan S, Moritz RL, Zhu HJ, Simpson RJ Tandem application of cationic colloidal silica and Triton X-114 for plasma membrane protein isolation and purification: Towards developing an MDCK protein database Proteomics. 11, 1238-53, 2011
  15. 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
  16. Kim K. Ia, Grace R. Jeschke, Sheng Liu, Hong-Jian Zhu, Bruno Catimel, Benjamin E. Turk and Heung-Chin Cheng Defining the substrate specificity determinants recognized by the active site of C-terminal Src kinase-Homologous Kinase (CHK) and Identification of β-Synuclein as a Potential CHK Physiological Substrate, Biochemistry, 50, 6667-77, 2011
  17. Heung-Chin Cheng, Robert Z Qi, Hemant Paudel, Hong-Jian Zhu Regulation and function of protein kinases and phosphatases, Enzyme Research 01/2011; 2011:794089. DOI: 10.4061/2011/794089, 2011
  18. Rodney B. Luwor, Xiaowen Chin, Andrew B. McGeachie, Phillip J. Robinson and Hong-Jian Zhu Dynamin II is Required for EGF-mediated Stat3 Activation but not Erk1/2 Phosphorylation, Growth Factors, 30, 220-9, 2012
  19. Robert J. J. O’Donoghue, Darryl A. Knight, Carl D. Richards, Cecilia M. Prêle, Hui Ling Lau, Andrew G. Jarnicki, Jessica Jones, Steven Bozinovski, Ross Vlahos, Stefan Thiem, Brent S. McKenzie, Bo Wang, Philip Stumbles, Geoffrey J. Laurent, Robin J. McAnulty, Stefan Rose-John, Hong Jian Zhu, Gary P. Anderson, Matthias R. Ernst, Steven E. Mutsaers Genetic partitioning of interleukin-6 signalling in mice dissociates Stat3 from Smad3-mediated lung fibrosis, EMBO Molecular Medicine, 4, 939-51, 2012
  20. Ardian Latifi, Rodney B. Luwor, Maree Bilandzic, Simon Nazaretian, Kaye Stenvers, Jan Pyman, Hongjian Zhu, Erik W. Thompson, Michael A. Quinn, Jock K. Findlay, Nuzhat Ahmed. Isolation and Characterization of Tumor Cells from the Ascites of Ovarian Cancer Patients: Molecular Phenotype of Chemoresistant Ovarian Tumors, PLoS ONE 7(10): e46858. doi:10.1371/journal.pone.0046858, 2012
  21. 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
  22. Nicholas Fleming, Robert Jorissen, Dmitri Mouradov, Michael Christie, Anuratha Sakthianandeswaren, Michelle Palmieri, Fiona Day, Shan Li, Cary Tsui, Lara Lipton, Jayesh Desai, Ian Jones, Stephen McLaughlin, Robyn Ward, Nicholas Hawkins, Andrew Ruszkiewicz, James Moore, Hong-Jian Zhu, John Mariadason, Tony Burgess, Dana Busam, Qi Zhao, Robert Strausberg, Peter Gibbs, and Oliver Sieber. SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer, Cancer Research, 73, 725-735, 2013
  23. Shields BJ, Wiede F, Gurzov EN, Wee K, Hauser C, Zhu HJ, Molloy TJ, O'Toole SA, Daly RJ, Sutherland RL, Mitchell CA, McLean CA, Tiganis T. TCPTP Regulates SFK and STAT3 Signaling and Is Lost in Triple-Negative Breast Cancers, Mol Cell Biol. 33(3):557-70, 2013
  24. Tauro BJ, Mathias RA, Greening DW, Gopal SK, Ji H, Kapp EA, Coleman BM, Hill AF, Kusebauch U, Hallows JL, Shteynberg D, Moritz RL, Zhu HJ, Simpson RJ, Oncogenic H-ras reprograms Madin-Darby canine kidney (MDCK) cell-derived exosomal proteins following epithelial-mesenchymal transition, Mol Cell Proteomics, 12(8):2148-59, 2013
  25. Ji H, Greening DW, Barnes TW, Lim JW, Tauro BJ, Rai A, Xu R, Adda C, Mathivanan S, Zhao W, Xue Y, Xu T, Zhu HJ, Simpson RJ. Proteome profiling of exosomes derived from human primary and metastatic colorectal cancer cells reveal differential expression of key metastatic factors and signal transduction components, Proteomics, 13(10-11):1672-86, 2013
  26. Abubaker K, Latifi A, Luwor R, Nazaretian S, Zhu H, Quinn MA, Thompson EW, Findlay JK, Ahmed N, Short-term single treatment of chemotherapy results in the enrichment of ovarian cancer stem cell-like cells leading to an increased tumor burden, Mol Cancer. 2013, 12:24. doi: 10.1186/1476-4598-12-24
  27. 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
  28. Nelson Ung, Tracy L. Putoczki, Stanley Stylli, Irvin Ng, John M. Mariadason, Timothy A. Chan, Hong-Jian Zhu and Rodney B. Luwor, Anti-EGFR Therapeutic Efficacy Correlates Directly with Inhibition of STAT3 Activity, Cancer Biology and Therapy, 15(5) 623-632, DOI:10.4161/cbt.28179 2014.
  29. Khalid Abubaker, Rodney B Luwor, Hongjian Zhu, Orla McNally, Michael A Quinn, Christopher J Burns, Erik W Thompson, Jock K Findlay and Nuzhat Ahmed, Inhibition of the JAK2/STAT3 pathway in ovarian cancer results in the loss of cancer stem cell-like characteristics and a reduced tumor burden, BMC Cancer, 14:317, 2014 (doi:10.1186/1471-2407-14-317)
  30. Maree Bilandzic , Yao Wang; Nuzhat  Ahmed; Rodney   Luwor; Hong J Zhu; Jock K Findlay ; Kaye  L Stenvers, Betaglycan blocks metastatic behaviors in human granulosa cell tumors by suppressing NFκΒ-mediated induction of MMP2, Cancer Letters, 354 (1): 107-114, 2014, doi:10.1016/j.canlet.2014.07.039,
  31. 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
  32. Jingyi Sheng, Weisan Chen and Hong-Jian Zhu, Immune suppression function of Transforming Growth Factor-β (TGF-β) in human diseases, Growth Factors, 2015, 33(2):1-10 DOI: 10.3109/08977194.2015.1010645
  33. David W. Greening, Shashi K. Gopal, Rommel A. Mathias, Lin Liu, Jingyi Sheng, Hong-Jian Zhu, Richard J. Simpson, Emerging roles of exosomes during epithelial-mesenchymal transition and cancer progression, Seminars in Cell and Developmental Biology, 2015, 40, 60-71 DOI: 10.1016/j.semcdb.2015.02.008
  34. 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.
  35. Shashi K. Gopal, David W. Greening, Rommel A. Mathias, Hong Ji, Maoshan Chen, Hong‐Jian Zhu, Richard J. Simpson, YBX1/YB-1 induces partial EMT and tumourigenicity in epithelial MDCK cells, Oncotarget, 2015, 6(15), 13718 -13730, DOI: 10.18632/oncotarget.3764
  36. Yeong-Chit Joel Chia, Bruno Catimel, Daisy Sio Seng Lio, Ching-Seng Ang, Benjamin Peng, Hong Wu, Hong-Jian Zhu, Heung-Chin Cheng, The C-terminal Tail Inhibitory Phosphorylation Sites of PTEN Regulate Its Intrinsic Catalytic Activity and the Kinetics of its Binding to Phosphatidylinositol-4,5-bisphosphate, Archives of Biochemistry and Biophysics, 2015, 587, 48-60, DOI: 10.1016/j.abb.2015.10.004
  37. SK Gopal, DW Greening, EG Hanssen, H-J Zhu, RJ Simpson, and RA Mathias, Oncogenic epithelial cell-derived exosomes containing Rac1 and PAK2 induce angiogenesis in recipient endothelial cells, Oncotarget, 2016, DOI: 10.18632/oncotarget.7573
  38. 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)

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


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