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.
Cancer Therapeutics and Stratified Oncology
The Cancer Therapeutics and Stratified Oncology group at the GIS uses a variety of advanced and contemporary technology platforms to generate and analyse high-quality multi-dimensional data sets associated with cancer, to answer fundamental questions concerning tumour cell death and survival. Our research programmes 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.
Cancer Stem Cell Biology
Malignant tumours are highly heterogeneous, consisting of cancer cells intermingled with blood vessels and stromal cells. The cancer cell population itself is also a constellation of different cell types contributing to the unique histopathological features of specific cancers. There is now substantial evidence that only a subpopulation of ‘tumour initiating cells’ are capable of proliferating, differentiating and maintaining tumour growth and phenotype. Tumour Initiating Cells (TICs), or Cancer Stem Cells (CSCs), first identified and characterised in leukemias, have been described in several solid tumours, including breast, colon, brain and prostate.
Most recently, we have described the isolation of TICs for lung adenocarcinoma. It is most likely that with careful experimental designs, TICs can be identified and isolated from all human cancers.
This has opened up new avenues to explore in our war against cancer. Our recent work with lung cancer TICs has, for example, revealed new and exciting therapeutic pathways and targets. The GIS cancer stem cell programme is built around a series of logical progressive steps:
- To develop methods to identify and isolate TICs from many different solid cancers (e.g. liver, pancreas, stomach).
- To fully characterise, at the cellular and molecular level, TICs from different tumours.
- To develop new strategies to eliminate each type of TICs, including identifying the most promising therapeutic targets.
- To rapidly evolve TIC-specific treatment modalities into clinical trials.
- To test the power of combining anti-TICs treatment with other treatment modalities.
Our ultimate goal is to discover new drugs that could, in combination with other drugs, eliminate TICs/CSCs in cancer. Our expectations are that research into the biology of TICs/CSCs will have a significant impact on improving the control and elimination of many cancers
Featured Publications
- Tan DE, Foo JN, Bei JX, Chang J, Peng R, Zheng X, Wei L, Huang Y, Lim WY, Li J, Cui Q, Chew SH, Ebstein RP, Kuperan P, Lim ST, Tao M, Tan SH, Wong A, Wong GC, Tan SY, Ng SB, Zeng YX, Khor CC, Lin D, Seow AL, Jia WH, Liu J. Genome-wide association study of B cell non-Hodgkin lymphoma identifies 3q27 as a susceptibility locus in the Chinese population. Nature Genetics. 2013;45(7):804-7.
- 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 Jr, 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. Nature Medicine. 2012;18(4):521-8.
- 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. Exome sequencing of gastric adenocarcinoma identifi es recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nature Genetics. 2012;44(5):570-4.
- Zhang WC, Shyh-Chang N, Yang H, Rai A, Umashankar S, Ma S, Soh BS, Sun LL, Tai BC, Nga ME, Bhakoo KK, Jayapal SR, Nichane M, Yu Q, Ahmed DA, Tan C, Sing WP, Tam J, Thirugananam A, Noghabi MS, Pang YH, Ang HS, Mitchell W, Robson P, Kaldis P, Soo RA, Swarup S, Lim EH, Lim B Glycine decarboxylase activity drives non- small cell lung cancer tumor-initiating cells and tumorigenesis. Cell. 2012 148(1-2):259-72.
- Fullwood MJ, Liu MH, Pan YF, Liu J, Xu H, Mohamed YB, Orlov YL, Velkov S, Ho A, Mei PH, Chew EG, Huang PY, Welboren WJ, Han Y, Ooi HS, Ariyaratne PN, Vega VB, Luo Y, Tan PY, Choy PY, Wansa KD, Zhao B, Lim KS, Leow SC, Yow JS, Joseph R, Li H, Desai KV, Thomsen JS, Lee YK, Karuturi RK, Herve T, Bourque G, Stunnenberg HG, Ruan X, Cacheux-Rataboul V, Sung WK, Liu ET, Wei CL, Cheung E, Ruan Y. An oestrogen- receptor-alpha-bound human chromatin interactome. Nature. 2009;462(7269):58-64.
- Tan J, Yang X, Zhuang L, Jiang X, Chen W, Lee PL, Karuturi RK, Tan PB, Liu ET, Yu Q. Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes & Development. 2007;21(9):1050-63.
- Wei CL, Wu Q, Vega VB, Chiu KP, Ng P, Zhang T, Shahab A, Yong HC, Fu Y, Weng Z, Liu J, Zhao XD, Chew JL, Lee YL, Kuznetsov VA, Sung WK, Miller LD, Lim B, Liu ET, Yu Q, Ng HH, Ruan Y. A global map of p53 transcription-factor binding sites in the human genome. Cell. 2006;124(1):207-19.