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Single-cell RNA-seq recognized the initiator of epithelial ovarian cancer recurrence

Oncogene volume 41, pages 895–906 (2022)Cite this article

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Abstract

Epithelial ovarian cancers (EOCs) are sensitive to chemotherapy but will ultimately relapse and develop drug resistance. The origin of EOC recurrence has been elusive due to intra-tumor heterogeneity. Here we performed single-cell RNA sequencing (scRNA-seq) in 13,369 cells from primary, untreated peritoneal metastasis, and relapse tumors. We used time-resolved analysis to chart the developmental sequence of cells from the metastatic tumors, then traced the earliest replanting cells back to the primary tumors. We discovered seven distinct subpopulations in primary tumors where the CYR61+ “stress” subpopulation was identified as the relapse-initiators. Furthermore, a subpopulation of RGS5+ cancer-associated fibroblasts (CAFs) was found to strongly support tumor metastasis. The combined CYR61/RGS5 expression scores significantly correlated with the relapse-free-survival of EOC patients and can be used as predictors of EOC recurrence. Our study provides insights into the mechanism of EOC recurrence and presents CYR61+ relapse-initiating cells as potential therapeutic targets to prevent EOC relapse.

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Fig. 1: Dissection of EOC tumors with scRNA-seq.
Fig. 2: Identification of the initiation cells of metastatic tumors.
Fig. 3: Characterization of the metastatic-initiation cells.
Fig. 4: Trace the relapse-initiation cells to the primary tumors.
Fig. 5: Characterization of CAFs in EOC tumors.
Fig. 6: Correlation between CYR61/RGS5 expression levels with RFI of EOC.

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Data availability

Data generated for this study are available through the Gene Expression Omnibus (GEO,) accession number GSE130000.

Code availability

The version and parameters for the R packages used in this study are available in Methods and Supplementary Methods.

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Acknowledgements

We thank Dr Junhai Wang from Taian Tumor Prevention and Treatment Hospital for assistance with IHC. This work was supported by grants from the General Research Fund (CityU_11319516) and the Research Impact Fund (R1020-18F) of Hong Kong Research Grant Council, the Guangdong Frontier and Key Technology Development Fund (2017B020226001) of Guangdong Province, PR China, and the Knowledge Innovation Program (JCYJ20170818095453642 and JCYJ20180307123759162) of Shenzhen Municipality, PR China.

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Authors and Affiliations

  1. Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China

    Tongtong Kan, Feng Gao, Xin Wang & Mengsu Yang

  2. Beijing Institute of Basic Medical Sciences, Beijing, China

    Tongtong Kan

  3. Department of Pathology, The Second Affiliated Hospital of Shandong First Medical University, Taian, China

    Shupeng Zhang, Ya Zhang & Yinghua Gao

  4. Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second Hospital and State Key Laboratory of Biotherapy/Collaborative Innovation Center, West China Hospital, Sichuan University, Chengdu, China

    Shengtao Zhou & Linjie Zhao

  5. Department of Pathology, Taian Tumor Prevention and Treatment Hospital, Taian, China

    Yun Zhao

  6. Department of Biostatistics, School of Public Health, Shandong University, Jinan, China

    Tao Zhang

  7. Key Laboratory of Biochip Technology, Shenzhen Research Institute, City University of Hong Kong, Shenzhen, China

    Mengsu Yang

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Contributions

TK conceived the project, coordinated the collaboration, designed and performed the experiments, processed and analyzed the data, generated figures, and drafted and revised the paper. SZ provided the FFPE samples and supervisory support for histological study. SZ provided the fresh tumor samples for scRNA-seq. YZ and YZ checked the FFPE sample pathology and helped with the IHC experiments. YG checked the FFPE sample pathology and helped with the IHC imaging. TZ, FG, and XW provided computational support. LZ helped with collecting fresh tumor samples. MY supervised the project, revised the paper, and provided funding support to the project.

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Correspondence to Tongtong Kan or Mengsu Yang.

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Kan, T., Zhang, S., Zhou, S. et al. Single-cell RNA-seq recognized the initiator of epithelial ovarian cancer recurrence. Oncogene 41, 895–906 (2022). https://doi.org/10.1038/s41388-021-02139-z

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