--- breakthrough discoveries and clinical impact
Cancer represents a complex disease state where cellular interactions at multiple levels, including genetic, epigenetic, and transcriptomic, combine to establish a robust adaptive system that maintains cancer cell survival, even in the face of therapeutic interventions. Understanding the fundamental governing principles of this immense complexity is critical for developing novel and more effective treatments to inhibit cancer aggressiveness, metastasis, and drug resistance. The Cancer Therapeutics and Stratified Oncology group at the GIS uses a variety of advanced and contemporary technology platforms to generate and analyze high-quality multi-dimensional data sets associated with cancer, to answer fundamental questions concerning tumor cell death and survival. Our research programs integrate functional genomics, chemical biology, deep sequencing, and computational biology, interpreted through a systems biology perspective, to identify key elements critical to maintaining the biological phenotypes of cancer cells. Key areas of strength involve the identification of synthetic lethal gene-gene interactions, genomic alterations related to patient clinical outcome, and the development of novel strategies for cancer therapy.
Our team is also striving to translate our basic discoveries into applications for clinical impact. To this end, we have initiated POLARIS (Personalized OMIC Lattice for Advanced Research and Improving Stratification), a strategic initiative for introducing and embedding genomic information into the diagnosis and treatment of medical diseases in Singapore. Formed as a partnership between multiple A*STAR Research Institute and public healthcare centres, the POLARIS consortium will establish clinically certified genomic and metabolomic platforms, develop technologies for processing clinical samples, and develop informatic pipelines for results analysis, data interpretation, and clinician reporting. Through this effort, we seek to establish a unified national framework for the pursuit of "Clinical OMICS".
- Nagarajan N, Bertrand D, Hillmer AM, Zang ZJ, Yao F, Jacques PE, Teo AS, Cutcutache I, Zhang Z, Lee WH, Sia YY, Gao S, Ariyaratne PN, Ho A, Woo XY, Veeravali L, Ong CK, Deng N, Desai KV, Khor CC, Hibberd ML, Shahab A, Rao J, Wu M, Teh M, Zhu F, Chin SY, Pang B, So JB, Bourque G, Soong R, Sung WK, Tean Teh B, Rozen S, Ruan X, Yeoh KG, Tan PB, Ruan Y. (2012) Whole-genome reconstruction and mutational signatures in gastric cancer.Genome Biol. 2012 Dec 13;13(12):R115. [Epub ahead of print]
- Ng KP*, Hillmer AM*, Chuah CT*, Juan WC*, Ko TK, Teo AS, Ariyaratne PN, Takahashi N, Sawada K, Fei Y, Soh S, Lee WH, Huang JW, Allen JC, Woo XY, Nagarajan N, Kumar V, Thalamuthu A, Poh WT, Ang AL, Mya HT, How GF, Yang LY, Koh LP, Chowbay B, Chang CT, Nadarajan VS, Chng WJ, Than H, Lim LC, Goh YT, Zhang S, Poh D, Tan P, Seet JE, Ang MK, Chau NM, Ng QS, Tan DS, Soda M, Isobe K, Nöthen MM, Wong TY, Shahab A, Ruan X, Cacheux-Rataboul V, Sung WK, Tan EH, Yatabe Y, Mano H, Soo RA, Chin TM, Lim WT, Ruan Y, Ong ST "A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer." Nat Medicine. 2012 ; 18(4) : 521-8 Epub 2012 Mar 18
- Zang ZJ, Cutcutache I, Poon SL, Zhang SL, McPherson JR, Tao J, Rajasegaran V, Heng HL, Deng N, Gan A, Lim KH, Ong CK, Huang D, Chin SY, Tan IB, Ng CC, Yu W, Wu Y, Lee M, Wu J, Poh D, Wan WK, Rha SY, So J, Salto-Tellez M, Yeoh KG, Wong WK, Zhu YJ, Futreal PA, Pang B, Ruan Y, Hillmer AM, Bertrand D, Nagarajan N, Rozen S, Teh BT, Tan P. (2012) Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nat Genet. 44(5):570-4. [PMID 22484628]
- Sung WK, Zheng H, Li S, Chen R, Liu X, Li Y, Lee NP, Lee WH, Ariyaratne PN, Tennakoon C, Mulawadi FH, Wong KF, Liu AM, Poon RT, Fan ST, Chan KL, Gong Z, Hu Y, Lin Z, Wang G, Zhang Q, Barber TD, Chou WC, Aggarwal A, Hao K, Zhou W, Zhang C, Hardwick J, Buser C, Xu J, Kan Z, Dai H, Mao M, Reinhard C, Wang J, Luk JM. (2012) Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat Genet. 2012 May 27;44(7):765-9. doi: 10.1038/ng.2295.
- Shuet Theng Lee, Zhimei Li, Zhenlong Wu, Meiyee Aau, Peiyong Guan, R.K. Murthy Karuturi, Yih Cherng Liou and Qiang Yu ."Context-Specific Regulation of NF-kB Target Gene Expression by EZH2 in Breast Cancers". Molecular Cell, 43, 798–810, 2011.
- Tao J, Deng NT, Ramnarayanan K, Huang B, Oh HK, Leong SH, Lim SS, Tan IB, Ooi CH, Wu J, Lee M, Zhang S, Rha SY, Chung HC, Smoot DT, Ashktorab H, Kon OL, Cacheux V, Yap C, Palanisamy N, Tan P. (2011) CD44-SLC1A2 gene fusions in gastric cancer. Sci Transl Med. 3(77):77ra30. [PMID:21471434]
- Hillmer AM*, Yao F*, Inaki K*, Lee WH*, Ariyaratne PN, Teo AS, Woo XY, Zhang Z, Zhao H, Ukil L, Chen JP, Zhu F, So JB, Salto-Tellez M, Poh WT, Zawack KF, Nagarajan N, Gao S, Li G, Kumar V, Lim HP, Sia YY, Chan CS, Leong ST, Neo SC, Choi PS, Thoreau H, Tan PB, Shahab A, Ruan X, Bergh J, Hall P, Cacheux-Rataboul V, Wei CL, Yeoh KG, Sung WK, Bourque G, Liu ET, Ruan Y "Comprehensive long-span paired-end-tag mapping reveals characteristic patterns of structural variations in epithelial cancer genomes." Genome Res 2011 May ; 21(5) : 665-75 Epub 2011 Apr 5
- Jing Tan, Puay Leng Lee, Zhimei Li, Xia Jiang, Yaw Chyn Lim, Shing Chuan Hooi and Qiang Yu. B55β-associated PP2A complex controls PDK1-directed Myc signaling and modulates rapamycin sensitivity in colorectal cancer. Cancer Cell, 18:459-471, 2010
- Kumar P, Henikoff S, Ng PC. (2009) Predicting the effects of coding nonsynonymous variants on protein function using the SIFT algorithm Nature Protocols 4:1073-81.
- Xia Jiang, Jing Tan, Jingsong Li, Saul Kivimäe, Xiaojing Yang1 Li Zhuang, Puay Leng Lee, Mark TW. Chan, Lawrence Stanton, Edison T. Liu, Benjamin N.R.Cheyette and Qiang Yu. DACT3 is an epigenetic regulator of Wnt/β-catenin signaling in colorectal cancer and is a therapeutic target of histone modifications. Cancer Cell. 13:529, 2008.
- Xiaojing Yang, Min Feng, Xia Jiang, Zhenlong Wu, Meiyee AAu, Zhimei Li, and Qiang Yu. miR-449a and miR-449b are direct transcriptional targets of E2F1 and negatively regulate pRb-E2F1 activity through a feedback loop by targeting CDK6 and CDC25A. Genes & Development. 2009 23: 2388-2393.