Molecular Carcinogenesis

The Sabapathy lab is focused on understanding the mechanistic basis of cancer development and resistance to therapeutic drugs, and translating the findings to generate effective therapies for cancer. To this end, multiple, nationally funded projects are undertaken by the team, as described:

MOUSE MODELS FOR CANCERS

Based on our expertise in generating and analysing genetically modified mice, we have been focusing on: 1) Understanding the development of liver cancers, especially those that arise in conjunction with hepatitis B virus, so as to identify biomarkers for early detection, and altered molecular pathways for therapeutic targeting; 2) Generating mouse models to recapitulate the development of liposarcomas for testing novel treatment modalities; and 3) understanding the cellular basis of breast cancer development, with a particular focus on the role of the stromal microenvironment in contributing to breast neoplasms. The use of mouse as a model organism has provided us with significant advantages in our understanding of multiple cancer types.

TARGETING P53 FAMILY MEMBERS

p53 is the most commonly mutated gene in cancers, with over 50% of cancers expressing a mutant p53, which promotes cancer development and metastasis. However, due to enormous technical difficulties, there are currently no therapies available to target mutant p53. Our efforts over the years have led to the characterisation of the various p53 mutants identified in humans, which has led to the concept of the “rainbow of p53 mutants” (Figure 1), all of which display varying degrees of oncogenic potential. Based on this concept, we have developed novel, first-in-class mutation-specific antibodies that are useful in the clinical diagnosis of mutants. We are working towards utilising these antibodies, as well as mutation-specific siRNAs, to target mutant p53 to improve treatment. Similar work is also underway to understand the functions of p73, the homologue of p53, to target its oncogenic functions in tumours.

Figure 1: “Rainbow of p53 mutants”. This "rainbow” is based on the capacity of p53 mutants to differentially transactivate target genes when expressed on a p53-null background, except in the case of DBD-DN mutants, which relates to the heterozygous state. WT and mutant p53 monomers are represented in yellow and red, respectively. PF, partial function; p53RE, p53 response element; TFRE, transcription-factor response element.

Selected publications:

1. Tabanifar B, Moorthy A, Tsai HH, Kannan S, Verma CS, Sabapathy K. JNK mediates cell death by promoting the ubiquitination of the apurinic/apyrimidinic endonuclease APE1. Cell Rep. 2023 Sep 26;42(9):113123. doi: 10.1016/j.celrep.2023.113123. Epub 2023 Sep 12. PMID: 37703179. 
2. Le Minh G, Lucky SS, Pervaiz S, Ramadan K, Yeong J, Ong ST, Krishnan V, Cheok CF, Chng WJ, De Mel S, Wang X, Jeyasekharan AD, Tipgomut C, Kong LR, Sabapathy K, Chee CE, Itahana K, Taneja R, Lee SC. Charting New Paths in Cancer Research: Insights from the Frontiers in Cancer Science Conference 2024. Cancer Res. 2025 Aug 1;85(15):2784-2787. doi: 10.1158/0008-5472.CAN-25-2205. PMID: 40746070. 
3. Lau HSH, Tan VKM, Tan BKT, Sim Y, Quist J, Thike AA, Tan PH, Pervaiz S, Grigoriadis A, Sabapathy K. Adipose-enriched peri-tumoral stroma, in contrast to myofibroblast-enriched stroma, prognosticates poorer survival in breast cancers. NPJ Breast Cancer. 2023 Oct 20;9(1):84. doi: 10.1038/s41523-023-00590-7. PMID: 37863888; PMCID: PMC10589339. 
4. Li D, Kok CYL, Wang C, Ray D, Osterburg S, Dötsch V, Ghosh S, Sabapathy K. Dichotomous transactivation domains contribute to growth inhibitory and promotion functions of TAp73. Proc Natl Acad Sci U S A. 2024 May 21;121(21):e2318591121. doi: 10.1073/pnas.2318591121. Epub 2024 May 13. PMID: 38739802; PMCID: PMC11127001. 
5. Krueger C, Sabapathy K. p53 prophylactic therapy for cancer prevention. Cell Death Differ. 2025 Dec;32(12):2257-2268. doi: 10.1038/s41418-025-01538-z. Epub 2025 Jun 25. PMID: 40562832; PMCID: PMC12669783.