Biology subjects

Tan, D. S.

Publications and source records attributed to Tan, D. S..

4 recordsLinked to original sources

bioRxiv2026

Systematic benchmarking of multi-modal approaches for tumor-naive ctDNA detection and quantification

Longitudinal monitoring of circulating tumor DNA (ctDNA) has emerged as a promising framework for characterizing treatment response dynamics in cancer. Scalable tumor-naive approaches for quantifying ctDNA often involve whole-genome sequencing (WGS) or DNA methylation profiling, but their comparative performance and capacity for complementary integration remain poorly understood. Here we systematically benchmarked tumor-naive WGS- and methylation-based ctDNA quantification methods using plasma from 150 patients with colorectal, lung and breast cancer. Using paired high-depth WGS and EM-seq data, we generated 40,000 in silico samples and evaluated detection accuracy, limits of detection (LoD) and quantification (LoQ) across cancer types and sequencing depths (0.1x-30x). We further assessed single- and multimodal method combinations, identifying conditions under which integrated approaches enhance analytical performance for detection and quantification relative to single modalities. This benchmark delineates key performance trade-offs and provides a practical framework to support method development and guide future research applications in ctDNA-based biomarker studies.

bioinformatics↗

bioRxiv2022

Systems Biology Approach of Understanding Insulin Resistance: Linkage between Type 2 Diabetes and Alzheimer's Disease

Insulin resistance (IR) is a physiological condition in which cells in the body become resistant to insulin. It is a known risk factor associated to type 2 diabetes (T2D). Recently, the idea that IR plays an important role in the progression of Alzheimers disease (AD) has been gaining a lot of attention. Comparing the components of the insulin signalling pathway in relation to T2D and AD, there seems to be a lot of commonality. However, on what role IR plays in linking T2D and AD remains unknown. Through systems biology approach, we extended an existing mathematical model (i.e. ODE based) to study and understand the role IR plays in linking T2D and AD. The simulations, together with the experimental data collected from the literature, show that the common components in T2D and AD express the same dynamical behaviors. This result provides the bases for further modelling of the insulin signaling pathway in determining the link between T2D and AD.

systems biology↗

bioRxiv2020

Primary platinum resistance and immune exclusion in ovarian carcinomas with high expression of the homologous recombination mediator RAD51

BackgroundHomologous recombination deficiency (HRD) in ovarian cancer confers increased sensitivity to Poly-ADP-Ribose-Polymerase (PARP) inhibitors and platinum. The homologous recombination (HR) mediator RAD51, however, is commonly overexpressed, potentially driving unregulated HR. Due to non-quantitative measurements and heterogeneous cohorts, the clinical relevance of RAD51 expression in ovarian cancer is unclear. MethodsFluorescent immunohistochemistry and multispectral imaging were used to quantitate RAD51 expression, in relation to other markers, in independent cohorts of ovarian carcinomas from British Columbia Cancer (BCC n=284) and the phase III SCOTROC4 trial (n=268). Independent cohorts (TCGA n=566, GSE9891 n=267, GSE26712 n=185 and GSE3149 n=146) were used for mRNA expression and immune infiltration analyses. ResultsRAD51-High tumours had shorter progression-free and overall survival compared to RAD51-Low cases in both BCC and SCOTROC4. The negative prognostic significance of high RAD51 was primarily evident in cases classified "HRD negative" by the Myriad genomic scar assay. Unexpectedly, overexpression of RAD51 in ovarian cancer cell lines did not affect sensitivity to platinum or PARP inhibitors, but modified the expression of immune-regulatory genes. Accordingly, tumours with high RAD51 mRNA showed consistent changes in immunomodulatory transcripts across four independent ovarian cancer cohorts. In-situ multiplexed imaging confirmed that high RAD51 tumours correlated with tumour exclusion of cytotoxic-T-cells, possibly explaining their poor outcomes after chemotherapy. ConclusionsHigh RAD51 expression, in conjunction with a HRD score <42, identifies a subgroup of EOC cases with platinum resistance and an immune excluded tumour microenvironment. Tumours with high RAD51 may require alternate or additional adjuvant therapeutic strategies to overcome immune exclusion. Statement of Translational RelevanceHomologous recombination deficiency (HRD) in ovarian cancer confers increased sensitivity to Poly-ADP-Ribose-Polymerase (PARP) inhibitors and platinum. Currently, methods to identify patients who do poorly on first-line platinum based chemotherapy in ovarian cancer represent an unmet clinical need. In this report we show that RAD51 expression can identify patients with primary platinum resistance in two large cohorts, including a unique phase-III trial of carboplatin as adjuvant monotherapy. The clinical relevance of a positive genomic scar HRD score, a biomarker for assessing HRD status, in predicting benefit to PARP inhibitors has been established following recent phase 3 trials in first line and 2nd line maintenance treatment of ovarian cancer. Our findings suggest that HRD negative ovarian tumours may be further stratified by RAD51 expression status in the context of platinum sensitivity, and may serve to guide future trials of HRD targeted agents.

cancer biology↗

bioRxiv2018

Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia

The MUSASHI family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We found that the small molecule Ro 08-2750 (Ro) directly binds to MSI2 and competes for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemia cells resulted in an increase in differentiation and apoptosis, inhibition of known MSI-targets, and a shared global gene expression signature similar to shRNA depletion of MSI2. Ro demonstrated in vivo inhibition of c-MYC and reduced disease burden in a murine AML leukemia model. Thus, we have identified a small molecule that targets MSIs oncogenic activity. Our study provides a framework for targeting RNA binding proteins in cancer.

cancer biology↗