CSI PhD students bag multiple awards at YLLSoM Annual Graduate Scientific Congress

The NUS Yong Loo Lin School of Medicine 5th Annual Graduate Scientific Congress, a gathering of budding scientists, researchers and clinicians alike, took place on 27th January 2015 at the NUHS Tower Block Auditorium. A platform for graduate students to showcase the excellent research conducted over the course of their candidature, this year’s congress theme was centred on “Decoding Science, Translation Medicine”. CSI’s very own PhD students have performed exceedingly well, garnering a number of top awards over various categories.

Best Oral Presentation Award
Chin Wai Loon Desmond

Chin Wai Loon Desmond
Supervisor: Motomi Osato

RUNX1 haploinsufficiency results in granulocyte-colony stimulating factor hypersensitivity and leukemia predisposition

3rd Runner-up Oral Presentation Award

Wang Chao
Supervisor: Alan Prem Kumar

RNA Helicase DDX20, a Biomarker of Statin Activity in Invasive Breast Cancer

Statins, used for the treatment of hypercholesterolemia inhibit the rate-limiting enzyme of the mevalonate pathway, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). Interestingly, cancer cells are dependent on the sustained availability of this pathway and habor dysregulated expression of HMGCR. In several prospective studies, simvastatin use was associated with reduced risk of breast cancer. It is reported that statins inhibit proliferation and metastasis in a variety of cancers, including breast cancer by interfering with activation of NF-?B. Our group recently reported a novel oncogene, DDX20, as a crucial positive regulator of NF-?B activation and its target genes. In the present study, we first assessed correlation between 17 mevalonate pathway genes and expression of DDX20 in a cohort of 1325 breast cancer tumors. Among the 17 genes evaluated, positive correlation with DDX20 expression was observed in eight of them, with HMGCR having the most significant positive correlation. Our in vitro experiments show exposure of breast cancer cells to statins lead to a Rho-dependent decrease in expression of DDX20, leading to decreased tumor proliferation in a mevalonate pathway-dependent manner. Conversely, overexpression of DDX20 significantly abrogated the effects of statins. A similar observation was seen in a mouse model, where simvastatin fed mice show significantly decreased DDX20 and lung metastases, corroborating our observations in vitro. A long term implication of our findings is the possibility of an effective combinatorial therapeutic mesenchymal-like cells capable of dissemination to multiple organs. EMT is regulated by several transcription factors called EMT inducers in various physiological and pathological contexts. Snail1, Snail2, Twist, ZEB1 and ZEB2 are among the most potent inducers of EMT. Recent studies have shown that TIP60 down-regulation correlates with node positivity, metastasis, and poor survival rates. Yet the mechanism behind this correlation is remain unknown. We have used both in vitro and in vivo models to study role of TIP60 in EMT. I will be presenting data where we have identified the mechanism by which TIP60 acts as an inhibitor of EMT.

Best Research Publication Award

Meng Xuan
Supervisor: H Phillip Koeffler

The genomic landscape of nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) has extremely skewed ethnic and geographic distributions, is poorly understood at the genetic level and is in need of effective therapeutic approaches. Here we determined the mutational landscape of 128 cases with NPC using whole-exome and targeted deep sequencing, as well as SNP array analysis. These approaches revealed a distinct mutational signature and nine significantly mutated genes, many of which have not been implicated previously in NPC. Notably, integrated analysis showed enrichment of genetic lesions affecting several important cellular processes and pathways, including chromatin modification, ERBB-PI3K signaling and autophagy machinery. Further functional studies suggested the biological relevance of these lesions to the NPC malignant phenotype. In addition, we uncovered a number of new druggable candidates because of their genomic alterations. Together our study provides a molecular basis for a comprehensive understanding of, and exploring new therapies for, NPC.

Best Research Publication Award

Xu Liang
Supervisor: H Phillip Koeffler

Genomic and molecular characterization of esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is prevalent worldwide and particularly common in certain regions of Asia. Here we report the whole-exome or targeted deep sequencing of 139 paired ESCC cases, and analysis of somatic copy number variations (SCNV) of over 180 ESCCs. We identified previously uncharacterized mutated genes such as FAT1, FAT2, ZNF750 and KMT2D, in addition to those already known (TP53, PIK3CA and NOTCH1). Further SCNV evaluation, immunohistochemistry and biological analysis suggested their functional relevance in ESCC. Notably, RTK-MAPK-PI3K pathways, cell cycle and epigenetic regulation are frequently dysregulated by multiple molecular intervention using statins (to suppress DDX20 expression) and a suitable first-line agent for the treatment of invasive breast cancer.

Best Poster Presentation Award

Wang Xin
Supervisor: Edward Chow

Using nanodiamond for drug delivery in liver cancer treatment by adsorbing Epirubicin

Liver cancers are among the most common cancers worldwide and hepatocellular carcinomas (HCCs) account for 75% of all primary liver cancers. In HCCs, potential cancer stem cells (CSCs) have been identified through the isolation of side population (SP) cells according to the ability to efflux Hoechst 33343 dye. These SP cells share many functional properties of CSCs such as extensive self-renewal and proliferative capacity, and more importantly, the ability to initiate tumor growth in immuno-compromised mice. SP cells are also resistant to conventional chemotherapies and are the likely candidates for tumor recurrence owing to the ability to efflux drugs effectively via expression of various ABC drug transporters. Here, we proposed the use of a nanoparticle drug delivery platform, nanodiamonds (NDs) for targeting of these chemoresistant cells. Using ND adsorbed with a common chemotherapeutic agent, Epirubicin (Epi), we demonstrated that these EPND complex can prolong drug retention in tumor cells.  More importantly, we also showed that EPND complex can significantly reduce the SP cells as compared to Epirubicin drug alone. Finally, EPND showed significant lower toxicity than Epi. Collectively, ND-conjugated chemotherapy presents a promising avenue for overcoming chemoresistance in cancers.

Best Poster Presentation Award

Zhang Yanzhou
Supervisor: Sudhakar Jha

Role of TIP60 in Epithelial-Mesenchymal Transition

TIP60, HIV-Tat-interacting protein 60 KDa, is a lysine acetyltransferase involved in multiple cellular pathways, such as transcription regulation, DNA damage-induced checkpoint activation, and apoptosis. TIP60 also known to function as a haploinsufficient tumour suppressor and is down-regulated in multiple types of cancer, including those induced by viruses. Epithelial-mesenchymal transition (EMT) is considered as an important step in cancer metastasis, and describes the process whereby polarized, immotile epithelial cells convert to motile, invasive mechanisms in this cancer. Our approaches also uncovered many druggable candidates, and XPO1 was further explored as a therapeutic target because it showed both gene mutation and protein overexpression. Our integrated study unmasks a number of novel genetic lesions in ESCC and provides an important molecular foundation for understanding esophageal tumors and developing therapeutic targets.