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Background <p>Chemotherapy resistance remains a major clinical challenge in ovarian cancer treatment, limiting therapeutic efficacy and patient survival. Understanding the molecular mechanisms underlying chemoresistance at the single-cell level is crucial for developing targeted therapeutic strategies.</p> Methods <p>We performed comprehensive single-cell RNA sequencing analysis on primary and chemoresistant ovarian cancer samples to characterize cellular heterogeneity and identify resistance-associated molecular signatures. Cell type identification, differential gene expression analysis, functional enrichment analysis, and immune microenvironment characterization were conducted to elucidate chemoresistance mechanisms. Computational predictions were validated by RT-qPCR analysis of four key resistance genes (BIRC5, ABCB1A, ABCG2, BCL2) in SKOV3 and SKOV3-CDDP cell lines.</p> Results <p>Our analysis identified nine distinct cell populations within the ovarian cancer microenvironment, revealing extensive transcriptional reprogramming in chemoresistant tumors. Key chemoresistance genes including Abcb1a, Abcg2, Bcl2, Birc5, Nek2, Inhba, Irs1, and Prc1 showed differential expression patterns across cell types. Epithelial cells and proliferating cells exhibited elevated expression of multiple resistance markers, particularly Birc5. Functional analysis revealed enrichment of ribosome biogenesis, protein synthesis machinery, and amoeboid-type cell migration pathways in resistant cells. Macrophage polarization states were significantly altered, and immune checkpoint molecules showed coordinated upregulation, indicating comprehensive immune microenvironment reprogramming. RT-PCR validation confirmed single-cell predictions with significant upregulation in resistant cells: BIRC5 (4.2-fold, <i>p</i> &lt; 0.001), ABCB1A (3.8-fold, <i>p</i> &lt; 0.001), ABCG2 (2.9-fold, <i>p</i> &lt; 0.01), and BCL2 (2.1-fold, <i>p</i> &lt; 0.05).</p> Conclusions <p>This study provides a comprehensive single-cell atlas of chemoresistance in ovarian cancer, revealing cell type-specific resistance mechanisms and immune evasion strategies. The identified molecular signatures offer potential therapeutic targets for overcoming chemotherapy resistance and improving patient outcomes.</p>

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Single cell transcriptomic analysis reveals molecular mechanisms of chemoresistance and immune microenvironment remodeling in ovarian cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月18日

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  • Xia Hu,
  • Caifang Du,
  • Dongjie Du,
  • Yonghua Zhang,
  • Haijian Gao,
  • Minxian Tao

摘要

Background

Chemotherapy resistance remains a major clinical challenge in ovarian cancer treatment, limiting therapeutic efficacy and patient survival. Understanding the molecular mechanisms underlying chemoresistance at the single-cell level is crucial for developing targeted therapeutic strategies.

Methods

We performed comprehensive single-cell RNA sequencing analysis on primary and chemoresistant ovarian cancer samples to characterize cellular heterogeneity and identify resistance-associated molecular signatures. Cell type identification, differential gene expression analysis, functional enrichment analysis, and immune microenvironment characterization were conducted to elucidate chemoresistance mechanisms. Computational predictions were validated by RT-qPCR analysis of four key resistance genes (BIRC5, ABCB1A, ABCG2, BCL2) in SKOV3 and SKOV3-CDDP cell lines.

Results

Our analysis identified nine distinct cell populations within the ovarian cancer microenvironment, revealing extensive transcriptional reprogramming in chemoresistant tumors. Key chemoresistance genes including Abcb1a, Abcg2, Bcl2, Birc5, Nek2, Inhba, Irs1, and Prc1 showed differential expression patterns across cell types. Epithelial cells and proliferating cells exhibited elevated expression of multiple resistance markers, particularly Birc5. Functional analysis revealed enrichment of ribosome biogenesis, protein synthesis machinery, and amoeboid-type cell migration pathways in resistant cells. Macrophage polarization states were significantly altered, and immune checkpoint molecules showed coordinated upregulation, indicating comprehensive immune microenvironment reprogramming. RT-PCR validation confirmed single-cell predictions with significant upregulation in resistant cells: BIRC5 (4.2-fold, p < 0.001), ABCB1A (3.8-fold, p < 0.001), ABCG2 (2.9-fold, p < 0.01), and BCL2 (2.1-fold, p < 0.05).

Conclusions

This study provides a comprehensive single-cell atlas of chemoresistance in ovarian cancer, revealing cell type-specific resistance mechanisms and immune evasion strategies. The identified molecular signatures offer potential therapeutic targets for overcoming chemotherapy resistance and improving patient outcomes.