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Neuro-Oncology Research Laboratory

NNI Dr Christopher Ang Beng Ti Carol Tang.jpg

Christopher Ang Beng Ti (Left)

MBBS (1993), FRCSEd (1999) FRCSGlasg (1999), FRCSEd (SN) (2006)
Senior Consultant, Department of Neurosurgery / Clinical Investigator
Co-Principal Investigator, Neuro-Oncology Research Laboratory 

Carol Tang, Ph.D. (Right)

The Scripps Research Institute, 1998 (Macromolecular and Cellular Structure and Chemistry)
Co-Principal Investigator,
Neuro-Oncology Research Laboratory

Contact Information

Neuro-Oncology Research Laboratory
National Neuroscience Institute
11 Jalan Tan Tock Seng, Singapore 308433
Tel: (65) 6357 7616 (Office) / (65) 6357 7634 (Lab)
Fax: (65) 6256 9178
Email: beng_ti_ang@nni.com.sg, carol_tang@nni.com.sg

The Team

  • Edwin Sandanaraj, MSc (Bioinformatician)
  • Tan Boon Toh, BSc Hons (Graduate Student)
  • Yuk Kien Chong, BSc (Graduate Student)
  • Lynnette Koh, BSc Hons (Senior Research Assistant)
  • Melanie Tan, BSc Hons (Senior Research Assistant)
  • Moogaambikai Thangaveloo (Senior Research Assistant)

NNI Neuro-Oncology Research Laboratory.jpg

Overview

Glioma-Propagating Cells: Clinical Relevance

Our laboratory first started in June 2005 with a focus on the establishment of patient-derived glioma-propagating cells (GPCs) (Chong et al, Stem Cells, 2009). These stem-like cells exhibit many of the hallmarks of the primary tumor: stemness/multipotentiality markers, karyotype and transcriptomic profile. Importantly, we and others showed that orthotopic xenografts established from GPCs recapitulate the pathophysiology of the patient’s original tumor. Furthermore, we showed that GPCs established from patient tumors with similar histology are transcriptomically distinct, highlighting the limitation of histology to diagnose and subsequently treat patients. Indeed several works which were recently published from our laboratory, further supported the advancement of genomic technologies in assessing brain tumors (Choudhury et al, J Clin Invest, 2012; Ng et al, Clin Cancer Res, 2012; Yeo et al, Cancer Res, 2012).

NNI Glioma-Propagating Cells.jpg

We showed that GPCs isolated from major brain tumor variants, oligodendrogliomas and glioblastoma multiforme (GBM), contain gene expression pathway networks that dictate primary tumor behavior (Ng et al, Clin Cancer Res, 2012). Interestingly, our GPC-derived gene signature predicted patient survival more robustly than current clinical indicators of age, histology and the 1p/19q co-deletion status, underscoring the molecular heterogeneity of the disease. Our findings are important as they validate future studies utilizing patient-derived GPCs as a clinically relevant cellular platform (Figure 1).

Tumor Cell Invasiveness

NNI Tumor Cell Invasiveness.jpg

Brain tumors such as glioblastomas are notoriously aggressive, with a high recurrence rate resulting in part from the invasiveness of tumor cells. In a collaborative effort with the National University of Singapore (Associate Professor Shu Wang) to unravel novel mechanisms governing tumor cell invasiveness, we identified reduced editing of miR-376a* in high-grade human glioma samples, as well as their target genes, and this correlated with a higher tumor volume on patient magnetic resonance imaging scans (Figure 2) (Choudhury et al, J Clin Invest, 2012). Lower levels of adenosine-to-inosine editing of mRNAs have been observed in some cancers, particularly in high-grade gliomas. Our work combining basic science, genomic interrogation and clinical data sheds light on the functional consequences of miR-376 editing, and suggests that this miRNA editing and target alteration pathway could be relevant in human cancer.

Chemoresistance: Elevated O2-:H2O2 Ratio as a Prosurvival Advantage

Moving further, we studied the nature of drug resistance by focusing on reactive oxygen species, specifically the superoxide and hydrogen peroxide molecules; in press . We formulated the ROS Index as a quantitative measure of O2-:H2O2 ratio, and showed its ability to predict the propensity for drug-induced apoptosis, an advance in a previously qualitative redox biology field. Furthermore, depletion of this Index sensitized GPCs to apoptotic triggers, and prolonged tumor latency and extended survival in mouse orthotopic models. Strikingly, patients with gene expression programs associated with reduced ROS Index tended to have a more favorable prognosis, providing firm evidence that tilting the balance between O2- and H2O2 can constitute a viable treatment strategy.

Mouse Model

In addition to the orthotopic xenograft models used in our lab, we, together with Associate Professor Lim Kah Leong, are also exploring lineage-tracing mouse models to evaluate the role of Parkin as a tumor suppressor in glioma (Yeo et al, Cancer Res, 2012). We remain very excited at the possibility of translating our findings in a clinical setting, while combining basic science knowledge at unraveling the etiology of the disease through transgenic mouse modeling.

Selected Publications

  1. Li, S., Wang, C., Sandanaraj, E., Aw, S. S., Koe, C. T., Wong, J. J., Yu, F., Ang, B. T., Tang, C. & Wang, H. The SCFSlimb E3 ligase complex regulates asymmetric division to inhibit neuroblast overgrowth. EMBO Rep (2014).
  2. Koh, L., Koh, G., Ng, F., Toh, T. B., Sandanaraj, E., Chong, Y. K., Phong, M., Tucker-Kellogg, G., Kon, O. L., Ng, W. H., Ng, I., Clement, M. V., Pervaiz, S., Ang, B. T. & Tang, C. A Distinct Reactive Oxygen Species Profile confers Chemoresistance in Glioma-Propagating Cells and Associates with Patient Survival Outcome. Antioxid Redox Signal 19, 2261-2279 (2013).
  3. Choudhury, Y., Tay, F. C., Lam, D. H., Sandanaraj, E., Tang, C., Ang, B. T. & Wang, S. Attenuated adenosine-to-inosine editing of microRNA-376a* promotes invasiveness of glioblastoma cells. J Clin Invest 122, 4059-4076 (2012).
  4. Foong, C. S., Sandanaraj, E., Brooks, H. B., Campbell, R. M., Ang, B. T., Chong, Y. K. & Tang, C. Glioma-Propagating Cells as an In Vitro Screening Platform: PLK1 as a Case Study. J Biomol Screen 17, 1136-1150 (2012).
  5. Ng, F. S., Toh, T. B., Ting, E. H., Koh, G. R., Sandanaraj, E., Phong, M., Wong, S. S., Leong, S. H., Kon, O. L., Tucker-Kellogg, G., Ng, W. H., Ng, I., Tang, C. & Ang, B. T. Progenitor-like Traits Contribute to Patient Survival and Prognosis in Oligodendroglial Tumors. Clin Cancer Res 18, 4122-4135 (2012).
  6. Yeo, C. W., Ng, F. S., Chai, C., Tan, J. M., Koh, G. R., Chong, Y. K., Koh, L. W., Foong, C. S., Sandanaraj, E., Holbrook, J. D., Ang, B. T., Takahashi, R., Tang, C. & Lim, K. L. Parkin pathway activation mitigates glioma cell proliferation and predicts patient survival. Cancer Res 72, 2543-2553 (2012).
  7. Foong, C. S., Ng, F. S., Phong, M., Toh, T. B., Chong, Y. K., Tucker-Kellogg, G., Campbell, R. M., Ang, B. T. & Tang, C. Cryopreservation of cancer-initiating cells derived from glioblastoma. Front Biosci (Schol Ed) 3, 698-708 (2011).
  8. Tay, S. P., Yeo, C. W., Chai, C., Chua, P. J., Tan, H. M., Ang, A. X., Yip, D. L., Sung, J. X., Tan, P. H., Bay, B. H., Wong, S. H., Tang, C., Tan, J. M. & Lim, K. L. Parkin enhances the expression of cyclin-dependent kinase 6 and negatively regulates the proliferation of breast cancer cells. J Biol Chem 285, 29231-29238 (2010).
  9. Chong, Y. K., Toh, T. B., Zaiden, N., Poonepalli, A., Leong, S. H., Ong, C. E., Yu, Y., Tan, P. B., See, S. J., Ng, W. H., Ng, I., Hande, M. P., Kon, O. L., Ang, B. T. & Tang, C. Cryopreservation of neurospheres derived from human glioblastoma multiforme. Stem Cells 27, 29-39 (2009).
  10. Wang, C., Chang, K. C., Somers, G., Virshup, D., Ang, B. T., Tang, C., Yu, F. & Wang, H. Protein phosphatase 2A regulates self-renewal of Drosophila neural stem cells. Development 136, 2287-2296 (2009).
  11. Zhao, H., Tang, C., Cui, K., Ang, B. T. & Wong, S. T. A screening platform for glioma growth and invasion using bioluminescence imaging. Laboratory investigation. J Neurosurg 111, 238-246 (2009).
  12. Chua, C., Zaiden, N., Chong, K. H., See, S. J., Wong, M. C., Ang, B. T. & Tang, C. Characterization of a side population of astrocytoma cells in response to temozolomide. J Neurosurg 109, 856-866 (2008).
  13. Tang, C., Ang, B. T. & Pervaiz, S. Cancer stem cell: target for anti-cancer therapy. FASEB J 21, 3777-3785 (2007).
  14. Tang, C., Chua, C. L. & Ang, B. T. Insights into the cancer stem cell model of glioma tumorigenesis. Ann Acad Med Singapore 36, 352-357 (2007).