Cancer-associated fibroblasts-derived FMO2 as a biomarker of macrophage infiltration and prognosis in epithelial ovarian cancer.
Cancer-associated fibroblasts-derived FMO2 as a biomarker of macrophage infiltration and prognosis in epithelial ovarian cancer.
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癌相关成纤维细胞衍生的FMO2作为上皮性卵巢癌中巨噬细胞浸润及预后的生物标志物
DOI：
10.1016/j.ygyno.2022.09.003
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发表时间：
2022-09
影响因子：
4.7
通讯作者：
Sihui Yu;Rui Yang;Tianhan Xu;Xi Li;Sufang Wu;Jiawen Zhang
中科院分区：
文献类型：
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作者：
Sihui Yu;Rui Yang;Tianhan Xu;Xi Li;Sufang Wu;Jiawen Zhang
最近的分子分析显示，癌症相关成纤维细胞（CAFs）对基质重塑和肿瘤进展至关重要。本研究旨在探讨含黄素单加氧酶2 （FMO2）作为一种新型的caf衍生预后生物标志物在上皮性卵巢癌（EOC）中的作用。方法分离原代成纤维细胞。检索微解剖和单细胞RNA测序（scRNA-seq）数据集（包括TCGA、GSE9891、GSE63885、GSE118828和GSE178913）以确定表达谱。采用基因集富集分析（GSEA）探讨FMO2与基质活化及免疫浸润的相关性。在独立的EOC队列（n= 113）中验证了FMO2和联合巨噬细胞浸润水平的预测价值。结果FMO2在肿瘤基质中表达上调，并与成纤维细胞激活相关。FMO2对EOC患者临床预后较差具有预测作用。在EOC的间充质亚型中，FMO2定义的特征显示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+细胞浸润水平呈正相关，并表明FMO2表达与肿瘤间质中CD163+细胞浸润水平结合可预测较差的总生存率（HR = 3.63, 95% CI = 1.93-6.84,p= 0.0008）。此外，FMO2还可以通过免疫检查点（如PD-L1和PD1）的表达来预测卵巢癌患者的预后。结论FMO2在EOC中的肿瘤支持作用及其与免疫成分的关联，可能是面向基质治疗EOC的潜在靶点。
ObjectiveRecent 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.MethodsPrimary 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).ResultsWe 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).ConclusionOur 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.