Research

Our recent discovery of impairment of ectodomain (extracellular domain) shedding due to reduced activity of the respective sheddases (membrane-bound proteases) in diabetic eye diseases (Alli-Shaik et al. , Theranostics) is a breakthrough as it will fill a major treatment gap in retinal angiogenic diseases. Our non-conventional novel approaches including a novel data analytics tool for tracking anomalous protein shedding activities, is a paradigm shift in investigating effective therapeutics. We currently focus on developing sheddase-centric molecular therapeutic modalities for neovascularization, inflammation and fibrosis in eye and other diseases. 

Key publications

• Alli-Shaik, Asfa, et al. "System-wide vitreous proteome dissection reveals impaired sheddase activity in diabetic retinopathy." Theranostics 12.15 (2022): 6682.

Our in-house cancer proteomics projects unveiled novel insights into cancer heterogeneity and associated mechanisms (Coffill et al. EMBO Reports; Gunaratne et al. J Biol Chem; Swa et al. Mol Cell Proteomics & Proteomics, Alli-Shaik et al. Breast Cancer Res.; Lim et al, Cancer Lett; Kosok et al, iScience). In-depth analysis of breast cancer proteomics big data from multiple ethnic groups and Singapore cohort tumour proteomics data through in-house developed novel computational pipelines (ProteoGrate, unpublished; FlexStat, De Silva, Bioinfom Adv.; UMAI, De Silva, Nat. Data Sci.) has uncovered dysregulation of proteins associated with extracellular matrix integrity (disordered matrisome) in highly aggressive breast cancer sub-type. We extend this study to decode molecular behaviours in cancer metastatic spread through strategized proximity proteomics-based interactomics and understudied posttranslational modification mapping. Furthermore, we will employ in-house developed proteomics assays adapted from our targeted proteomics-based single-shot flavivirus assay (Wee et al, PNAS) for high throughput monitoring of downstream signaling.

Key publications

• Coffill, Cynthia R., et al. "Mutant p53 interactome identifies nardilysin as a p53R273H‐specific binding partner that promotes invasion." EMBO reports 13.7 (2012): 638-644.

• Gunaratne, Jayantha, et al. "Protein interactions of phosphatase and tensin homologue (PTEN) and its cancer-associated G20E mutant compared by using stable isotope labeling by amino acids in cell culture-based parallel affinity purification." Journal of Biological Chemistry 286.20 (2011): 18093-18103.

• Swa, Hannah LF, et al. "Quantitative proteomics profiling of murine mammary gland cells unravels impact of annexin-1 on DNA damage response, cell adhesion, and migration." Molecular & Cellular Proteomics 11.8 (2012): 381-393.

• Alli-Shaik, Asfa, et al. "Phosphoproteomics reveals network rewiring to a pro-adhesion state in annexin-1-deficient mammary epithelial cells." Breast Cancer Research 19 (2017): 1-15.

• Lim, Jia Pei, et al. "Silencing Y-box binding protein-1 inhibits triple-negative breast cancer cell invasiveness via regulation of MMP1 and beta-catenin expression." Cancer letters 452 (2019): 119-131.

• Kosok, Max, et al. "Comprehensive proteomic characterization reveals subclass-specific molecular aberrations within triple-negative breast cancer." Iscience 23.2 (2020).

Cell surface markers, mainly overexpressed plasma membrane proteins with receptor characteristics, serve as viable targets for drugs and valuable biomarkers for distinguishing between various cellular phenotypes and disease states. Our lab has contributed to several cancer biology projects on proteomics discovery of surface biomarkers. Among them, our strategic surface proteomics approaches allowed identifying overexpression of surface protein, Agrin in hepatocellular carcinoma, which is an attractive target for antibody therapy (Chakraborty et al, Nat Commun.) and several surface markers in multiple myeloma (Xie et al, oncotarget). We develop novel and improved workflows from sample preparation to data analytics to capture and prioritize draggable surface markers and qualified surface proteins for antibody drug-conjugates.

Key publications

• Chakraborty, Sayan, et al. "An oncogenic role of Agrin in regulating focal adhesion integrity in hepatocellular carcinoma." Nature communications 6.1 (2015): 6184.

• Xie, Zhigang, et al. "Plasma membrane proteomics identifies biomarkers associated with MMSET overexpression in T (4; 14) multiple myeloma." Oncotarget 4.7 (2013): 1008.

One of our major research domains is to portrait soluble extracellular proteome, primarily biofluid proteomes in human diseases, to capture secreted protein markers with diagnostic and prognostic importance. One of such studies led to discover a highly specific and sensitive urine marker panel for diagnosis of transitional bladder carcinoma (international patents & licenced to local Biotech; Kumar et al, Onoctarget). Our established pipelines allow screening and validation of protein markers in serum/plasma for various diseases, vitreous/aqueous/tear markers for a range of eye diseases, salivary marker for Hand Food & Mouth Diseases (Tan et al, J Med Virol.) and to name a few.

Key publications

• Kumar, Prashant, et al. "Highly sensitive and specific novel biomarkers for the diagnosis of transitional bladder carcinoma." Oncotarget 6.15 (2015): 13539.

• Tan, Yong Wah, et al. "Potential relevance of salivary legumain for the clinical diagnostic of hand, foot, and mouth disease." Journal of Medical Virology 95.11 (2023): e29243.