Cancer Signaling Research Laboratory
Cancer Signalling Research Laboratory focuses on how molecular signalling pathway, particularly TGF-b signalling regulates each different stages of cancer development from initiation and growth to dissemination by invasion, circulation and metastatic seeding. More importantly, we translate out fundamental novel findings into therapeutic opportunities.
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 “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. It is clear that TGF-β signalling is a major molecular driver for cancer progression, particularly invasion and metastasis and the TGF-b targeted therapies are on-target and show good efficacies in pre-clinical tumour models. The chanllenge is to find the gaps between animal models and human cancer patients and ensure successful clinical treatment outcomes. 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 is 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 cover 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.
Ms Josie Iaria, Research Officer
Dr Thomas Ware, Postdoctoral Fellow
Mr Muhammad Murad, PhD student
Mr Adilson Fonseca Teixeira, PhD student
Ms Vania Gavrila Wikasa, Master of Biomedical Science student
Ms Fei (Cindy) Xu, Master of Biomedical Science student
Ms Siqi (Kelly) Wu, Master of Biomedical Science student
Professor Peter ten Dijke, Leiden University Medical Centre, The Netherlands
Professor HuiYao Lan, Hong Kong Chinese University, Hong Kong
Professor Kate Loveland, Monash University and Monash Medical Research Institute
Professor Tony Burgess and Dr Oliver Sieber, The Walter and Eliza Hall Institute of Medical Research
Professor Richard Simpson and Prof Weisan Chen, Latrobe University
Associate Professor Heung-Chin Cheng, The University of Melbourne
Zegenics (Melbourne, Australia)
Huagene Biomedics (Nanjing, China)
View Dr Hong-Jian Zhu's latest PubMed publications here
1. 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
2. Jingyi Sheng, Weisan Chenand Hong-Jian Zhu, The 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
3. 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
4. Rodney B. Luwor, Dulani Hakmana, Josephine Iaria, Thao V Nheu, Richard J Simpson and Hong-Jian Zhu, Single Live Cell TGF-b 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
5. 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
6. 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
7. 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
8. 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 126(4):1152-1162 DOI: 10.1172/JCI81129
9. Shashi Gopal, David Greening, Hong-Jian Zhu, Richard Simpson, and Rommel Mathias, Transformed MDCK cells secrete elevated MMP1 that generates LAMA5 fragments promoting endothelial cell angiogenesis, Scientific Reports 2016 DOI: 10.1038/srep28321.
10.Shashi K. Gopal, David W. Greening, Alin Rai, Maoshan Chen, Rong Xu, Adnan Shafiq, Rommel A. Mathias1, Hong-Jian Zhu and Richard J. Simpson, Extracellular vesicles: their role in cancer biology and epithelial–mesenchymal transition, Biochemical Journal 2017 474 21–45
11. J. Gourlay, A.P. Morokoff, R.B. Luwor, H.-J. Zhu, A.H. Kaye and S.S. Stylli The emergent role of exosomes in glioma, Journal of Clinical Neuroscience 2016 DOI: 10.1016/j.jocn.2016.09.021
12. Shabnam Khatibi, Hong-Jian Zhu, John Wagner, Chin Wee Tan, Jonathan H. Manton and Antony W. Burgess Mathematical model of TGF-β signalling: feedback coupling is consistent with signal switching BMC Systems Biology 2017 11:48, DOI: 10.1186/s12918-017-0421-5
13. Shabnam Khatibi , Jeff Babon, John Wagner, Jonathan H. Manton, Chin Wee Tan, Hong-Jian Zhu, Sam Wormald and Antony W. Burgess TGF-β and IL-6 family signalling crosstalk: an integrated model Growth Factors 2017 35(2-3):100-124
14. Gahana Advani, Ya Chee Lim, Bruno Catimel, Daisy Sio Seng Lio, Nadia L. Y. Ng, Anderly C. Chüeh, Mai Tran, Mohd Ishtiaq Anasir, Heather Verkade, Hong-Jian Zhu, Benjamin E. Turk, Thomas E. Smithgall, Ching-Seng Ang, Michael Griffin and Heung-Chin Cheng, Csk-homologous kinase (Chk) is an efficient inhibitor of Src-family kinases but a poor catalyst of phosphorylation of their C-terminal regulatory tyrosine. Cell Communication and Signaling 2017 15(1):29, DOI:10.1186/s12964-017-0186-x
15.Hao Chen, Thomas M.B. Ware, Josephine Iaria, and Hong-Jian Zhu Live cell imaging of the TGF-β/Smad3 signalling pathway in vitro and in vivo using an adenovirus reporter system Journal of Visualized Experiments 2018 (137), DOI: 10.3791/57926
16. Sheng Liu, Josephine Iaria, Richard J Simpson and Hong-Jian Zhu Ras enhances TGF-β signaling by decreasing cellular protein levels of its type II receptor negative regulator SPSB1 Cell Communication and Signaling 2018 16(1), DOI: 10.1186/s12964-018-0223-4
17. Thomas Ware and Hong-Jian Zhu Glioblastoma treatment: Where to now? Integrative Cancer Science and Therapeutics 2018 (ICST) 5(3):1-4, DOI: 10.15761/ICST.1000280
18. Fiona H. Tan, Tracy L. Putoczki, Jieqiong Lou, Elizabeth Hinde, Frederic Hollande, Julie Giraud, Stanely S Stylli, Lucia Paradiso, Hong-Jian Zhu, Oliver M Sieber and Rodney B Luwor Ponatinib Inhibits Multiple Signaling Pathways Involved in STAT3 Signaling and Attenuates Colorectal Tumor Growth Cancers 2018 10(12):526, DOI: 10.3390/cancers10120526
19. Jiang Ren , Marcel Smid , Josephine Iaria , Daniela C. F. Salvatori , Hans van Dam , Hong Jian Zhu , John W. M. Martens and Peter ten Dijke Cancer-associated fibroblast-derived Gremlin 1 promotes breast cancer progression, Breast Cancer Research 2019, 21:109
20. Yong‐Ke You, Qi Luo, Wei‐Feng Wu, Jiao‐Jiao Zhang, Hong‐Jian Zhu, Lixing Lao, Hui Y. Lan, Hai‐Yong Chen, Yong‐Xian Cheng Petchiether A attenuates obstructive nephropathy by suppressing TGF‐β/Smad3 and NF‐κB signalling, J Cell Mol Med. 2019, 23:5576–5587 DOI: 10.1111/jcmm.14454
21. Sijia Liu, Román González Prieto, Mengdi Zhang, Paul P. Geurink, Raymond Kooij, Prasanna Vasudevan Iyengar, Maarten van Dinther, Erik Bos, Xiaobing Zhang, Sylvia Le Dévédec, Bob van de Water, Roman I. Koning, Hong-Jian Zhu, Wilma Mesker, Alfred Vertegaal, Huib Ovaa, Long Zhang, John W. M. Martens, Peter ten Dijke, Deubiquitinase activity profiling identifies UCHL1 as a candidate oncoprotein that promotes TGFβ-induced breast cancer metastasis, Clinical Cancer Research, 2019, 26 (6), 1460-1473
22. Thomas Ware and Hong-Jian Zhu USP26 regulates TGF-β signalling by deubiquitinating and stabilizing SMAD7; not applicable in Glioblastoma, EMBO Report, 2020, 21 (1), e47030 DOI 10.15252/embr.201847030
23. Lipi Shukla, Rodney Luwor, Matthew E Ritchie, Shiva Akbarzadeh, Hong-Jian Zhu, Wayne Morrison, Tara Karnezis, Ramin Shayan, Therapeutic Reversal of Radiotherapy Injury to Pro-fibrotic Dysfunctional Fibroblasts In Vitro Using Adipose-derived Stem Cells, Plastic and Reconstructive Surgery Global Open, 2020, 8(3), e2706 doi: 10.1097/GOX.0000000000002706
24. Teixeira AF, ten Dijke P and Zhu H-J (2020) On-Target Anti-TGF-b Therapies Are Not Succeeding in Clinical Cancer Treatments: What Are Remaining Challenges? Front. Cell Dev. Biol. 8:605. doi: 10.3389/fcell.2020.00605
25. Jiang Ren, Yanhong Wang, Thomas Ware, Josephine Iaria, Peter Ten Dijke, Hong-Jian Zhu, Reactivation of BMP signaling by suboptimal concentrations of MEK inhibitor and FK506 reduces organ-specific breast cancer metastasis, Cancer Letters, 2020, https://doi.org/10.1016/j.canlet.2020.07.042
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