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Cancer-associated fibroblasts-derived FMO2 as a biomarker of macrophage infiltration and prognosis in epithelial ovarian cancer

  • Author Footnotes
    1 These authors contributed equally.
    Sihui Yu
    Footnotes
    1 These authors contributed equally.
    Affiliations
    Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China

    Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
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  • Author Footnotes
    1 These authors contributed equally.
    Rui Yang
    Footnotes
    1 These authors contributed equally.
    Affiliations
    Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
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  • Tianhan Xu
    Affiliations
    Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
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  • Xi Li
    Affiliations
    Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
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  • Sufang Wu
    Correspondence
    Corresponding authors at: Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No.650, Xin Songjiang Road, Shanghai, China.
    Affiliations
    Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
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  • Jiawen Zhang
    Correspondence
    Corresponding authors at: Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No.650, Xin Songjiang Road, Shanghai, China.
    Affiliations
    Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China

    Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
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  • Author Footnotes
    1 These authors contributed equally.
Published:September 13, 2022DOI:https://doi.org/10.1016/j.ygyno.2022.09.003

      Highlights

      • FMO2 contributed to the infiltration of macrophage.
      • Combination of FMO2 expression with CD163+ cell infiltration in stroma could predict poor overall survival.
      • FMO2 predicted the prognosis of patients with ovarian cancer based on the expression of immune checkpoints.

      Abstract

      Objective

      Recent molecular profiling revealed that cancer-associated fibroblasts (CAFs) are essential for matrix remodeling and tumor progression. Our study aimed to investigate the role of flavin-containing monooxygenase 2 (FMO2) in epithelial ovarian cancer (EOC) as a novel CAF-derived prognostic biomarker.

      Methods

      Primary fibroblasts were isolated from EOC samples. Microdissection and single-cell RNA sequencing (scRNA-seq) datasets (including TCGA, GSE9891, GSE63885, GSE118828 and GSE178913) were retrieved to determine the expression profiles. Gene set enrichment analysis (GSEA) was used to explore the correlation between FMO2 and stromal activation as well as immune infiltration. The predictive value of FMO2 and combined macrophage infiltration level was verified in an independent EOC cohort (n = 113).

      Results

      We demonstrated that FMO2 was upregulated in tumor stroma and correlated with fibroblast activation. Besides, FMO2 had the predictive power for worse clinical outcome of EOC patients. In the mesenchymal subtype of EOC, the FMO2-defined signature revealed that FMO2 contributed to infiltration of tumor-infiltrating lymphocytes. Moreover, we confirmed the positive correlation between FMO2 and CD163+ cell infiltration level in EOC tissues, and showed that combination of FMO2 expression with CD163+ cell infiltration level in the tumor stroma could predict poor overall survival (HR = 3.63, 95% CI = 1.93–6.84, p = 0.0008). Additionally, FMO2 also predicted the prognosis of patients with ovarian cancer based on the expression of immune checkpoints (such as PD-L1 and PD1).

      Conclusion

      Our results address the tumor-supporting role of FMO2 in EOC and its association with immune components, and it might be a prospective target for stroma-oriented therapies against EOC.

      Keywords

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