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.
Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
Gynecol Oncol. 2022 Nov;167(2):342-353. doi: 10.1016/j.ygyno.2022.09.003. Epub 2022 Sep 14.
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.
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).
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).
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.
最近的分子谱分析显示，癌症相关成纤维细胞（CAFs）对于基质重塑和肿瘤进展至关重要。本研究旨在探讨黄素单加氧酶 2（FMO2）在卵巢上皮癌（EOC）中的作用，将其作为一种新的 CAF 衍生的预后生物标志物。
从 EOC 样本中分离原代成纤维细胞。检索微切割和单细胞 RNA 测序（scRNA-seq）数据集（包括 TCGA、GSE9891、GSE63885、GSE118828 和 GSE178913）以确定表达谱。基因集富集分析（GSEA）用于探索 FMO2 与基质激活和免疫浸润之间的相关性。在独立的 EOC 队列（n = 113）中验证了 FMO2 和巨噬细胞浸润水平的预测价值。
我们证明 FMO2 在肿瘤基质中上调，并与成纤维细胞激活相关。此外，FMO2 对 EOC 患者的临床结局具有预测能力。在 EOC 的间质亚型中，FMO2 定义的特征表明 FMO2 有助于肿瘤浸润淋巴细胞的浸润。此外，我们证实了 FMO2 与 EOC 组织中 CD163 细胞浸润水平之间的正相关，并表明肿瘤基质中 FMO2 表达与 CD163 细胞浸润水平的组合可以预测总体生存率不良（HR = 3.63，95%CI = 1.93-6.84，p = 0.0008）。此外，FMO2 还基于免疫检查点（如 PD-L1 和 PD1）的表达预测了卵巢癌患者的预后。
我们的研究结果表明 FMO2 在 EOC 中的肿瘤支持作用及其与免疫成分的关联，它可能是针对 EOC 的基质定向治疗的有前途的靶点。
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