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Identification of Drug-resistant Cell Subpopulations in Colorectal Cancer Through Single-cell Analysis and
Yiquan Chen1, Da Wang1,2
1Liangzhu Laboratory & Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 311121, People's Republic of China.
Introduction:
The therapeutic efficacy of Colorectal Cancer (CRC) is often compromised by resistance to the standard chemotherapy agent oxaliplatin.
Methods:
This study obtained single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) database. Differentially Expressed Genes (DEGs) between resistant and sensitive epithelial subpopulations were identified, followed by enrichment analysis. Pseudotemporal trajectory and cell-cell communication were analyzed using Monocle2 and CellChat, respectively. The candidate drug was predicted by Connectivity Map (cMAP) analysis. External validation included assessment of the EpC2 signature in an oxaliplatin-resistant cell line dataset (GSE76092), survival analysis using The Cancer Genome Atlas (TCGA) cohorts, and re-analysis of the GSE179784 dataset to assess the reproducibility of EpC2-like subpopulations and their DNA Damage Repair (DDR) scores.
Results:
Cell subpopulations were divided into 10 clusters. Among them, epithelial cells comprised 5 subpopulations, with EPC2 identified as a potential oxaliplatin-resistant subset. DEGs were enriched in the TNF and IL-17 pathways. External validation confirmed the enrichment of EpC2 in resistant cell lines and its association with poor survival. Pseudotemporal trajectory revealed that epithelial cells underwent state transitions, forming two distinct branches. The resistant group exhibited enrichment in RNA splicing and NF-κB pathways. Cell-cell communication analysis revealed interactions involving MDK- NCL and PPIA-BSG. Dasatinib was predicted as a candidate drug.
Discussion:
We identified an oxaliplatin-resistant subpopulation of Epithelial Cells (EpC2) in CRC, elucidated its multi-layered resistance mechanisms, and integrated multi- omics and cMAP database analyses to predict a potential intervention drug.
Conclusion:
This study provided potential therapeutic possibilities for oxaliplatin resistance, contributing to CRC treatment.
Insights
Researchers identified a specific colorectal cancer cell subpopulation (EpC2) resistant to oxaliplatin chemotherapy. This discovery offers new therapeutic strategies to overcome drug resistance in colorectal cancer patients.
Area of Science:
- Oncology
- Genomics
- Bioinformatics
Background:
- Colorectal cancer (CRC) treatment efficacy is often limited by resistance to oxaliplatin chemotherapy.
- Identifying mechanisms of oxaliplatin resistance is crucial for developing effective CRC therapies.
Purpose of the Study:
- To identify and characterize oxaliplatin-resistant cell subpopulations in colorectal cancer.
- To elucidate the molecular mechanisms underlying oxaliplatin resistance.
- To predict potential therapeutic interventions for overcoming oxaliplatin resistance.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) was used to analyze CRC tissues.
- Differentially expressed genes (DEGs) between resistant and sensitive subpopulations were identified.
- Pseudotemporal trajectory, cell-cell communication, and Connectivity Map (cMAP) analyses were performed.
- External validation using independent datasets and survival analysis was conducted.
Main Results:
- A distinct epithelial cell subpopulation, EpC2, was identified as oxaliplatin-resistant.
- DEGs in EpC2 cells were enriched in TNF and IL-17 signaling pathways.
- EpC2 enrichment correlated with poor patient survival and resistance in cell lines.
- Dasatinib was predicted as a potential drug to overcome oxaliplatin resistance.
Conclusions:
- An oxaliplatin-resistant EpC2 subpopulation in CRC was identified.
- Multi-omics analyses revealed resistance mechanisms involving RNA splicing and NF-κB pathways.
- Dasatinib holds promise as a therapeutic agent for oxaliplatin-resistant CRC.
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