Dr. Cynthia (Cindy) Coffill leads the Discovery Group and focusses on modulation of the p53 pathway by small molecules, functional determination of p53 variants of unknown significance (VUS) among patient derived cellular samples as well the functional evolution of the p53 and HDM2 family members of different species. These studies are accomplished through a number of local and international collaborations as well as in-house experimental techniques, including high-throughput screens of small molecules; structure activity relationship (SAR) investigations; resistance studies using whole genome knockouts by CRISPR; proteome and binding partner investigations by mass spectrometry; tissue culture phenotypic screens; cell signalling pathway elucidation; molecular biology; cloning; qPCR; FACS and assay designs.
Cindy received her PhD from the University of Ottawa in Canada before joining the Universal Science College in Kathmandu, Nepal as an Assistant Professor in the Department of Biochemistry. She joined A*STAR in 2008 as a Research Fellow in cell biology in Walter Blackstock’s mass spectrometry lab and then transitioned to the p53 Laboratory in 2012 as a Senior Research Fellow and was promoted a Research Scientist in 2016.
Dr. Tan Ban Xiong received his PhD from the National University of Singapore for work on harnessing wild type p53 in acute myeloid leukaemia. He joined the p53 Laboratory in 2013 as a Research Fellow, and subsequently became a Senior Research Fellow. Ban Xiong contributed to the understanding of the roles of HDM2 and HDM4 in the regulation of wild type p53, a major tumour suppressor critical in preventing cancer formation. He is involved in the development and characterisation of novel stapled peptide antagonists of HDM2 and HDM4 in the treatment of acute myeloid leukaemia and other cancers where TP53 mutations are rare. His interests also include developing these peptides into drugs that exploit the p53 pathway in the treatment of skin diseases.
Dr. Teresa Ho:
What triggers cancer? The answer still eludes us decades on from the official declaration of 'War on Cancer' in 1971. Efforts so far have taught us that cancer is a product of multiple, sequential and highly variable mutagenic processes that culminate in a cell acquiring 'hallmarks' of cancer such as unlimited proliferative potential, evasion of apoptotic cues and self-sufficiency in growth signals. Furthermore, recent large-scale genomic studies have found that underlying burdens of somatic mutations are surprisingly high in certain tissues and that functionally and morphologically normal cells can harbor a multitude of oncogenic mutations or 'sins' that leave them poised for transformation.
How then can we resolve such diverse complexity and alter a cell's disease trajectory?
Teresa’s work focuses on:
- Understanding the dynamic interactions between different cell populations within a tumor and devising innovative ways to uncover shared traits that tip the scales in favor of tumorigenesis
- Studying the mechanisms by which these shared traits contribute to cancer outcomes from a genome stability angle
- Exploiting these shared traits with targeted therapies
- Studying the extent to which the immune, stromal and microbial environment dictates interactions between different cell populations within a tumor
To achieve this, patient-derived 3D organoid systems are employed in order to recapitulate tissue-specific and developmental constraints. In addition, CRISPR-based approaches, genotypic and phenotypic screens and multi-omics methods to query population-based dynamics are also used.
Cindy Coffill – Group Leader
Ban Xiong Tan – Senior Research Fellow
Teresa Ho – Research Fellow
Hui Chin Goh – Senior Research Officer
Ong JFM, Goh HC, Lim SC, Pang LM, Chin JSF, Tan KS, Liang ZX, Yang L, Glukhov E, Gerwick WH, and Tan LT. (2019) Integrated Genomic and Metabolomic Approach to the Discovery of Potential Anti-Quorum Sensing Natural Products from Microbes Associated with Marine Samples from Singapore. Mar Drugs. 17: pii: E72.
Ding CYG, Ong JFM, Goh HC, Coffill CR, and Tan LT. (2018) Benderamide A, a Cyclic Depsipeptide from a Singapore Collection of Marine Cyanobacterium Lyngbya. Marine Drugs. 16: pii: E409.
Ho T and Lane DP. (2018) Guardian of Genome Editing. CRISPR J. 1: 258-260.
Tan BX, Liew HP, Chua JS, Ghadessy FJ, Tan YS, Lane DP, and Coffill CR. (2017) Anatomy of Mdm2 and Mdm4 in evolution. J Mol Cell Biol. 9: 3-15
Schubert L, Ho T, Hoffmann S, Haahr P, Guérillon C, and Mailand N. (2017) RADX interacts with single-stranded DNA to promote replication fork stability. EMBO Rep. 18: 1991-2003
Goh HC, Sobota RM, Ghadessy FJ and Nirantar S. (2017). Going Native: Complete removal of protein purification affinity tags by simple modification of existing tags and proteases. Protein Expression and Purification 129: 18-24.
Goh HC, Ghadessy FJ and Nirantar S. (2017). Protein and Protease Sensing by Allosteric Depression. Methods in Molecular Biology, 1596: 167-177.
Zheng S, Koh XY, Goh HC, Rahmat SAB, Hwang LA and Lane DP. (2017). Inhibiting p53 Acetylation Reduces Cancer Chemotoxicity. Cancer Research, 77: 4342-4354.
Siau JW, Coffill CR, Zhang WV, Tan YS, Hundt J, Lane D, Verma C, and Ghadessy F. (2016) Functional characterization of p53 pathway components in the ancient metazoan Trichoplax adhaerens. Sci Rep. 6: 33972.
Coffill CR, Lee AP, Siau JW, Chee SM, Joseph TL, Tan YS, Madhumalar A, Tay BH, Brenner S, Verma CS, Ghadessy FJ, Venkatesh B, and Lane DP. (2016) The p53-Mdm2 interaction and the E3 ligase activity of Mdm2/Mdm4 are conserved from lampreys to humans. Genes Dev. 30: 281-92.
Haahr P, Hoffmann S, Tollenaere MA, Ho T, Toledo LI, Mann M, Bekker-Jensen S, Räschle and M, Mailand N. (2016). Activation of the ATR kinase by the RPA-binding protein ETAA1. Nat Cell Biol. 18: 1196-1207.
Ho TLF, Guilbaud G, Blow JJ, Sale JE, and Watson CJ. (2016) The KRAB Zinc Finger Protein Roma/Zfp157 Is a Critical Regulator of Cell-Cycle Progression and Genomic Stability. Cell Rep. 15: 724-734.
Lau YH, Wu Y, Rossmann M, Tan BX, de Andrade P, Tan YS, Verma C, McKenzie GJ, Venkitaraman AR, Hyvönen M, Spring DR. (2015) Double Strain-Promoted Macrocyclization for the Rapid Selection of Cell-Active Stapled Peptides. Angew Chem Int Ed Engl. 54: 15410-3.
Tan BX, Brown CJ, Ferrer FJ, Yuen TY, Quah ST, Chan BH, Jansson AE, Teo HL, Nordlund P, Lane DP. (2015) Assessing the Efficacy of Mdm2/Mdm4-Inhibiting Stapled Peptides Using Cellular Thermal Shift Assays. Sci Rep. 5: 12116.
Tan BX, Khoo KH, Lim TM, Lane DP (2014) High Mdm4 levels suppress p53 activity and enhance its half-life in acute myeloid leukaemia. Oncotarget 5: 933-43.
Muller PA, Trinidad AG, Timpson P, Morton JP, Zanivan S, van den Berghe PV, Nixon C, Karim SA, Caswell PT, Noll JE, Coffill CR, Lane DP, Sansom OJ, Neilsen PM, Norman JC, Vousden KH. (2013). Mutant p53 enhances MET trafficking and signalling to drive cell scattering and invasion. Oncogene. 32: 1252-65.
Coffill CR, Muller PA, Oh HK, Neo SP, Hogue KA, Cheok CF, Vousden KH, Lane DP, Blackstock WP, Gunaratne J. (2012) Mutant p53 interactome identifies nardilysin as a p53R273H-specific binding partner that promotes invasion. EMBO Rep. 13: 638-4.
Goh AM, Coffill CR, Lane DP. (2011). The role of mutant p53 in human cancer. J Pathol. 223: 116-26.