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Updated: Jun 13, 2025
Discovery of Driver Genes in Colorectal HT29-derived Cancer Stem-Like Tumorspheres
Published on: July 22, 2020
Integrative genomic and single-cell framework identifies druggable targets for colorectal cancer precision therapy
Yanggang Hong1,2, Jiajun Li1,2, Nuo Xu1
1State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Background:
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide. Despite therapeutic advances, there is a critical need to identify novel, effective, and safe drug targets to improve precision treatment strategies.
Methods:
We developed a multi-layered framework integrating Mendelian randomization (MR), colocalization analysis, genome-wide association study (GWAS) data, and expression quantitative trait loci (eQTLs) to prioritize causal and druggable genes in CRC. Single-cell and bulk RNA sequencing were used to characterize gene expression within the tumor microenvironment. Phenome-wide association studies (PheWAS) assessed off-target effects, and drug repurposing potential was evaluated using OpenTargets, DrugBank, and DGIdb. Validation of key targets was performed through RT-qPCR and immunohistochemistry (IHC) in CRC patient samples.
Results:
Out of 4,479 druggable genes, MR analysis identified 47 candidates significantly associated with CRC risk. Six genes (TFRC, TNFSF14, LAMC1, PLK1, TYMS, and TSSK6) demonstrated strong colocalization signals and were further validated across replication datasets and subtype-stratified analyses. PheWAS analysis revealed minimal off-target effects for these genes. Notably, several of these genes have already been targeted by existing or investigational drugs, suggesting potential for repurposing. These genes exhibited distinct expression patterns in tumor and stromal cell types and were differentially expressed in CRC versus normal tissues. Among them, TNFSF14, an immune modulator, is particularly involved in regulating T cell activation within the tumor microenvironment.
Conclusion:
This study identifies and validates six promising druggable targets for CRC, providing a strong foundation for future preclinical studies. These findings open avenues for advancing precision oncology and drug repurposing strategies in CRC treatment, contributing to the development of more effective and personalized therapeutic approaches.
Insights
This study identifies six promising druggable targets for colorectal cancer (CRC) using integrated genomic analyses. These validated targets offer potential for novel precision therapies and drug repurposing to improve patient outcomes.
Area of Science:
- Genomics
- Cancer Biology
- Pharmacology
Background:
- Colorectal cancer (CRC) is a major global health concern with significant mortality.
- Current treatments need improvement, highlighting the need for novel drug targets.
- Precision medicine strategies require identification of effective and safe therapeutic targets.
Purpose of the Study:
- To identify and validate druggable genes causally linked to colorectal cancer risk.
- To explore the potential for drug repurposing of identified targets.
- To characterize the expression patterns of candidate genes in the tumor microenvironment.
Main Methods:
- Integrated analysis of Mendelian randomization (MR), GWAS, eQTLs, and colocalization.
- Single-cell and bulk RNA sequencing for gene expression profiling.
- Phenome-wide association studies (PheWAS) for off-target effects and drug databases for repurposing potential.
Main Results:
- 47 candidate genes associated with CRC risk were identified from 4,479 druggable genes.
- Six genes (TFRC, TNFSF14, LAMC1, PLK1, TYMS, TSSK6) were validated with strong colocalization signals.
- These genes showed minimal off-target effects and distinct expression in tumor tissues, with TNFSF14 identified as an immune modulator.
Conclusions:
- Six novel druggable targets for colorectal cancer have been identified and validated.
- These targets hold promise for developing new precision oncology treatments and drug repurposing strategies.
- The findings provide a foundation for future preclinical research and improved CRC therapies.
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