Laboratory of Cancer Genomics

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Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide and presents a great public health and social burden. HCC is an epithelial cancer originating from hepatocytes and has been postulated to result from a series of genetic alterations attributable to a diverse range of causes. HCC is a highly therapyresistant cancer. Surgical treatments, including hepatic resection and orthotopic liver transplantation, provide the best option for cure in selected patients; yet, the long-term, disease-free survival rate remains unsatisfactory. Tumour recurrence and metastases are the major complications in more than two-thirds of these patients, with a poor prognosis and no proven effective survival-prolonging treatment modality available. There is indeed a great unmet need for new effective therapies for HCC. To tackle HCC, our laboratory employs unbiased, genome-wide strategies to identify key genes/regulatory pathways that are altered in relevant human HCC tissues. Further, we seek to understand how these changes affect the carcinogenesis of HCC, with the aim to modulate these regulatory pathways against the disease. We have systematically gathered molecular evidence and, through clinical corroboration of the data, have discovered molecular biomarkers that can provide clinically meaningful avenues for designing strategies independently from clinical risk factors. This, in turn, can be used to decipher the underlying molecular networks leading to HCC recurrence and identify reliable diagnostic and prognostic molecular biomarkers to develop novel therapeutics for HCC (Figure 1).

Selected publications:

1. The aberrant upregulation of exon 10-inclusive SREK1 through SRSF10 acts as an oncogenic driver in human hepatocellular carcinoma. Chang C, Rajasekaran M, Qiao Y, Dong H, Wang Y, Xia H, Deivasigamani A, Wu M, Sekar K, Gao H, Sun M, Niu Y, Li Q, Tao L, Yan Z, Wang M, Chen S, Zhao S, Chen D, Li L, Yang F, Gao H, Chen B, Su L, Xu L, Chen Y, Seshachalam VP, Chen G, Gunaratne J, Hong W, Shi J, Chen G, Grierson DS, Chabot B, Xie T, Hui KM, Chen J. Nat Commun. 2022 Mar 16;13(1):1363. 
2. STK39 is a novel kinase contributing to the progression of hepatocellular carcinoma by the PLK1/ERK signaling pathway. Chengfei Zhang, Xiaoming Wang, Dan Fang, Ping Xu, Xiao Mo, Chao Hu, Alaa Abdelatty, Mei Wang, Haojun Xu, Qi Sun, Guoren Zhou, Junjun She, Jinglin Xia, Kam Man Hui, Hongping Xia (Joint corresponding author). Theranostics. 2021; 11:2108-2122. 
   
3. Hypoxia-induced modulation of glucose transporter expression impacts 18F-fluorodeoxyglucose PET-CT imaging in hepatocellular carcinoma. Xia H, Chen J, Gao H, Kong SN, Deivasigamani A, Shi M, Xie T, Hui KM. Eur J Nucl Med Mol Imaging. 2020 Apr;47(4):787-797. 
4. Brusatol suppresses STAT3-driven metastasis by downregulating epithelial-mesenchymal transition in hepatocellular carcinoma. Lee JH, Mohan CD, Deivasigamani A, Jung YY, Rangappa S, Basappa S, Chinnathambi A, Alahmadi TA, Alharbi SA, Garg M, Lin ZX, Rangappa KS, Sethi G, Hui KM, Ahn KS. (Joint Corresponding author). J Adv Res. 2020 Jul 13;26:83-94. 
   
5. Clinical and metabolomics analysis of hepatocellular carcinoma patients with diabetes mellitus. Xia H, Chen J, Sekar K, Shi M, Xie T, Hui KM. Metabolomics. 2019 Nov 26;15(12):156. 
6. Genome-wide CRISPR knockout screens identify NCAPG as an essential oncogene for hepatocellular carcinoma tumor growth. Yu Wang, Bin Gao, Peng Yang Tan, Yohana Ayupriyanti Handoko, Karthik Sekar, Amudha Deivasigamani, Veerabrahma Pratap Seshachalam, Han-Yue OuYang, Ming Shi, Chan Xie, Brian Kim Poh Goh, London Lucien Ooi, and Kam Man Hui. FASEB J. 2019 Aug:33(8):8759-8770. 
   
7. NUF2 is a valuable prognostic biomarker to predict early recurrence of hepatocellular carcinoma after surgical resection. Wang Y, Tan PY, Handoko YA, Sekar K, Shi M, Xie C, Jiang XD, Dong QZ, Goh BKP, Ooi LL, Gao Z, Hui KM. Int J Cancer. 2019 Aug 1;145(3):662-670. 
8. CDK1-mediated BCL9 phosphorylation inhibits clathrin to promote mitotic Wnt signalling. Chen J, Rajasekaran M, Xia H, Kong SN, Deivasigamani A, Sekar K, Gao H, Swa HL, Gunaratne J, Ooi LL, Xie T, Hong W, Hui KM. EMBO J. 2018 Oct 15; 37(20). 
9. Organelle Specific O-Glycosylation Drives MMP14 Activation, Tumor Growth, and Metastasis. Anh Tuan Nguyen, Joanne Chia, Manon Ros, Kam Man Hui, Frederic Saltel, Frederic Bard. Cancer Cell. 2017; 32(5):639-653.e6.

Lab Unit of Paediatric Brain Tumour Research Office

The laboratory unit for the Paediatric Brain Tumour Research Office (PBTRO), SingHealth Duke-NUS Academic Medical Centre was established in 2015, with competitive grants secured. We are a dynamic laboratory unit and have steadily expanded our team and international collaborations over the past few years. Our goal in research is to derive findings that enable a reflective change in the practice of medicine in brain tumours. Our team (PBTRO) shares a common dream to present globally competitive research findings in the field of neurooncology, addressing these areas in the practice of medicine through science. We work on several types of brain tumours, both in paediatric and adult populations. One major research focus of our group is in the brain tumour microenvironment, translating research findings in tumour biology and genomics to bedside benefits for patients with brain tumours. Our research combines genomic methodologies and mouse models to study the complex regulation and developmental biology of brain tumours. We place a large emphasis on the preclinical development of therapeutics for brain tumours that currently have no cures, drawing from various strengths in genomics, high throughput functional assays optimised in our laboratory, and a large, unique cohort of patient-derived orthotopic mouse models of brain tumours developed for preclinical testing.

EXCERPT FROM PBTRO TEAM MEMBERS & INTERN STUDENTS

“Our work focuses on cell culture and utilises molecular techniques to unravel the cell biology behind the drug effects on brain tumours; this is in line with our team goal to discover effective and novel treatments for the benefit of patients.”

“The most important insight I learnt from this internship was realising the tenacity of character required to become a successful researcher. Their passion for their work, and their grit and perseverance constantly inspire me to work hard in my studies knowing that my study now is not as challenging as the lives of these researchers.”

Our Work at Laboratory 609-T, Laboratory Unit of Pediatric Brain Tumour Research Office, SingHealth Duke-NUS Academic Medical Centre

Selected publications:

1. Teo WY, Elghetany MT, Liu D, et al. Therapeutic implications of CD1d expression and tumor infiltrating macrophages in pediatric medulloblastomas. J Neurooncol. 2014;120:293–301. *
2. Teo WY, Ross J, Bollo RJ, et al. Atypical location and clinical behavior of nonteratomatous intracranial germ cell tumors in children. J Neurosurg Pediatr. 2014;25:1–8. * (Podcast highlight by the journal)
3. Teo WY, JMF Su, Shen JS, et al. Implications of tumor locations on subtypes of medulloblastoma (Priority Report with Commentary Highlight). Pediatr Blood Cancer. 2013;60:1408–1410.
4. Teo WY, Sekar K, Seshachalam P, Shen J, Chow WY, Lau CC, Yang H, Park J, Kang SG, Li X, Nam DH, Hui KM. Relevance of a TCGA-derived Glioblastoma Subtype Gene-Classifier among Patient Populations. Sci Rep. 2019 May 15;9(1):7442.* Top 100 Most Downloaded Cancer Articles in Scientific Reports in 2019. Metrics: Article downloaded 2031 times (19 March 2020)
5. Qi L, Kogiso M, Du Y, Zhang H, Braun FK, Huang Y, Teo WY, Lindsay H, Zhao S, Baxter P, Zhao X, Yu L, Liu Z, Zhang X, Su JM, Adesina A, Yang J, Chintagumpala M, Perlaky L, Tsz-Kwong Man C, Lau CC, Li XN. Impact of SCID mouse gender on tumorigenicity, xenograft growth and drug-response in a large panel of orthotopic PDX models of pediatric brain tumors. Cancer Lett. 2020 Sep 3:S0304-3835(20)30449-3. doi: 10.1016/j.canlet.2020.08.035. Online ahead of print
6. Teo WY. Implications for border containment strategies when COVID-19 presents atypically. Public Health. 2020 Jul 24;186:193-196. doi: 10.1016/j.puhe.2020.07.019.*
   
7. Yoon SJ, Son HY, Shim JK, Moon JH, Kim EH, Chang JH, Teo WY, Kim SH, Park SW, Huh YM, Kang SG. Co-expression of cancer driver genes: IDH-wildtype glioblastoma-derived tumorspheres. J Transl Med. 2020 Dec 14;18(1):482. doi: 10.1186/s12967-020-02647-8.
8. Elghetany MT, Ho JM, Shi-Qi LH, Karthik S, Su JMF, Lin Q, Du Y, Shen J, Chow WY, Lau CC, Adesina A, Major A, Erdreich-Epstein A, Hui KM, Li XN, Teo WY. Maximizing the potential of aggressive mouse tumor models in preclinical drug testing. Scientific Reports 2021 Jun 2;11(1):11580. doi: 10.1038/s41598-021-91167-6.* 
9. Huang Y, Qi L, Kogiso M, Du Y, Braun FK, Zhang H, Huang LF, Xiao S, Teo WY, Lindsay H, Zhao S, Baxter P, Su JMF, Adesina A, Yang J, Brabetz S, Kool M, Pfister SM, Chintagumpala M, Perlaky L, Wang Z, Zhou Y, Man TK, Li XN. Spatial Dissection of Invasive Front from Tumor Mass Enables Discovery of Novel microRNA Drivers of Glioblastoma Invasion. Adv Sci. 2021 Dec;8(23):e2101923. doi: 10.1002/advs.202101923. 
10. Roh TH, Lee JH, Kim SJ, Shim JK, Park J, Yoon SJ, Teo WY, Kim SH, Chang JH, Kang SG. A novel biguanide (IM1761065) inhibits bioenergetics of glioblastoma tumorspheres. J Neurooncol. 2022 Jan;156(1):139-151. doi: 10.1007/s11060-021-03903-7. 
11. Kogiso M, Qi L, Du Y, Braun FK, Zhang H, Huang LF, Guo L, Huang Y, Teo WY, Lindsay H, Zhao S, Injac SG, Liu Z, Mehta V, Tran D, Li F, Baxter PA, Su JM, Perlaky L, Parsons DW, Chintagumpala M, Adesina A, Song Y, Li XN. Synergistic anti-tumor efficacy of mutant isocitrate dehydrogenase 1 inhibitor SYC-435 with standard therapy in patient-derived xenograft mouse models of glioma. Transl Oncol. 2022 Apr;18:101368. doi: 10.1016/j.tranon.2022.101368.
    

*Denotes publications where Teo WY is a corresponding author