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Updated: Aug 4, 2025
Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer
Published on: August 2, 2024
Single-cell RNA-sequencing analysis reveals divergent transcriptome events between platinum-sensitive and
Zixun Wang1, Linlin Yang2,3,4, Xiaoye Su5
1Nanshan School, Guangzhou Medical University, Guangzhou, China.
Background:
Tumor resistance is one of the main reasons leading to the failure of ovarian cancer treatment. Overcoming platinum resistance remains the greatest challenge in the management of high-grade serous ovarian carcinoma (HGSC).
Methods:
Small conditional RNA-sequencing is a powerful method for exploring the complexity of the cellular components and their interactions in the tumor microenvironment. We profiled the transcriptomes of 35,042 cells from two platinum-sensitive and three platinum resistance HGSC clinical cases downloaded from Gene Expression Omnibus (GSE154600) and annotated tumor cells as platinum-resistant or sensitive based on the clinical trait. The study systematically investigated the inter-tumoral (using differential expression analysis, CellChat, and SCENIC) and intra-tumoral heterogeneity (using enrichment analysis such as gene set enrichment analysis, as well as gene set variation analysis, weighted gene correlation network analysis, and Pseudo-time analysis) of HGSC.
Results:
A cellular map of HGSC generated by profiling 30,780 cells was revisualized using Uniform Manifold Approximation and Projection. The inter-tumoral heterogeneity was demonstrated with intercellular ligand-receptor interactions of major cell types and regulons networks. FN1, SPP1, and COLLAGEN play important roles in the cross-talk between tumor cells and the tumor microenvironment. HOXA7, HOXA9_extended, TBL1XR1_extended, KLF5, SOX17, and CTCFL regulons consistent with the distribution of platinum-resistant HGSC cells were the high activity regions. The intra-tumoral heterogeneity of HGSC was presented with corresponding functional pathway characteristics, tumor stemness features, and the cellular lineage transition from platinum-sensitive to resistant condition. Epithelial-mesenchymal transition played an important role in platinum resistance, whereas oxidative phosphorylation was the opposite. There was a small subset of cells in platinum-sensitive samples that had transcriptomic characteristics similar to platinum-resistant cells, suggesting that the progression of platinum resistance in ovarian cancer is inevitable.
Conclusions:
The present study describes a view of HGSC at single-cell resolution that reveals the characteristics of the HGSC heterogeneity and provides a useful framework for future investigation of platinum-resistant.
Insights
Platinum resistance is a major hurdle in ovarian cancer treatment. This study reveals that platinum resistance in high-grade serous ovarian carcinoma (HGSC) involves complex cellular interactions and inevitable progression, offering insights for future therapies.
Area of Science:
- Oncology
- Genomics
- Bioinformatics
Background:
- Platinum resistance significantly limits treatment efficacy in high-grade serous ovarian carcinoma (HGSC).
- Overcoming platinum resistance is a critical challenge in managing HGSC, necessitating a deeper understanding of its underlying mechanisms.
Purpose of the Study:
- To investigate the inter-tumoral and intra-tumoral heterogeneity of HGSC at single-cell resolution.
- To identify key cellular interactions and molecular pathways contributing to platinum resistance in HGSC.
- To explore the cellular lineage and progression from platinum-sensitive to platinum-resistant states.
Main Methods:
- Profiling transcriptomes of 35,042 cells from platinum-sensitive and resistant HGSC clinical cases using single-cell RNA sequencing.
- Utilizing differential expression analysis, CellChat, SCENIC, GSEA, GSVA, WGCNA, and pseudo-time analysis to investigate heterogeneity.
- Revisualizing a cellular map of HGSC using Uniform Manifold Approximation and Projection.
Main Results:
- Identified key cross-talk molecules (FN1, SPP1, COLLAGEN) between tumor cells and the tumor microenvironment.
- Highlighted active regulons (HOXA7, HOXA9, TBL1XR1, KLF5, SOX17, CTCFL) associated with platinum-resistant HGSC.
- Demonstrated the role of epithelial-mesenchymal transition in platinum resistance and oxidative phosphorylation in sensitivity.
- Observed transcriptomic similarities between a subset of platinum-sensitive cells and platinum-resistant cells, suggesting inevitable resistance progression.
Conclusions:
- Provided a single-cell resolution view of HGSC heterogeneity, revealing characteristics of platinum resistance.
- Established a framework for future investigations into platinum-resistant HGSC.
- Suggested that the progression towards platinum resistance in ovarian cancer may be an inevitable process.
