Christopher Ang Beng Ti (Left)
MBBS (1993), FRCSEd (1999) FRCSGlasg (1999), FRCSEd (SN) (2006)Senior Consultant, Department of Neurosurgery / Clinical InvestigatorCo-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
Neuro-Oncology Research LaboratoryNational Neuroscience Institute11 Jalan Tan Tock Seng, Singapore 308433 Tel: (65) 6357 7616 (Office) / (65) 6357 7634 (Lab) Fax: (65) 6256 9178 Email: firstname.lastname@example.org, email@example.com
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).
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
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.
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.
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