Ma Ying, Xue Fengqin, Pei Zhihua, Zhao Ye
Department of Gynecology, The First Hospital of Shanxi Medical University, Taiyuan, China.
Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan, China.
Exp Cell Res. 2025 Jun 23:114656. doi: 10.1016/j.yexcr.2025.114656.
Drug resistance contributes to the relatively low 5-year survival rate in ovarian cancer patients. Due to the complex cell-cell interactions in the tumor microenvironment, the mechanism of drug resistance is highly intricate. Here, we aim to establish 3-dimensional (3D) organotypic co-cultures of primary ovarian cancer-derived organoids with cancer-associated fibroblasts (CAFs) and to understand their interactions and the response to treatment.
CAFs and organoids were isolated from tissues of a patient with high-grade serous ovarian cancer, and a 3D co-culture model of organoids with CAFs was established in vitro. The organoid growth and drug sensitivity were compared with and without the presence of CAFs. Gene expression analysis was conducted to identify the key genes and pathways leading to the phenotypic changes.
We successfully constructed a 3D co-culture model of human ovarian cancer organoids with CAFs. CAFs have been observed to promote organoids growth and protect them from paclitaxel and cisplatin treatment. Transcriptome analysis suggested that CAFs may mediate organoid growth and promote resistance through multiple pathways, including the PI3K-Akt signaling pathway and cytokine-cytokine receptor interaction. Additionally, patients with high ovarian CAF signature exhibited a poor prognosis in three public ovarian cancer cohorts.
In conclusion, this study demonstrates that the integration of CAFs into an ovarian cancer organoid culture model results in the promotion of tumor growth and the mediation of resistance through multiple signaling pathways. This provides a reliable research model for elucidating the mechanisms underlying drug resistance in ovarian cancer and the development of targeted therapies.
耐药性导致卵巢癌患者的5年生存率相对较低。由于肿瘤微环境中复杂的细胞间相互作用，耐药机制高度复杂。在此，我们旨在建立原发性卵巢癌来源的类器官与癌相关成纤维细胞（CAFs）的三维（3D）器官型共培养体系，并了解它们之间的相互作用以及对治疗的反应。
从一名高级别浆液性卵巢癌患者的组织中分离出CAFs和类器官，在体外建立类器官与CAFs的3D共培养模型。比较有无CAFs时类器官的生长和药物敏感性。进行基因表达分析以确定导致表型变化的关键基因和途径。
我们成功构建了人卵巢癌类器官与CAFs的3D共培养模型。观察到CAFs可促进类器官生长，并保护它们免受紫杉醇和顺铂治疗的影响。转录组分析表明，CAFs可能通过多种途径介导类器官生长并促进耐药性，包括PI3K-Akt信号通路和细胞因子-细胞因子受体相互作用。此外，在三个公开的卵巢癌队列中，卵巢CAF特征高的患者预后较差。
总之，本研究表明，将CAFs整合到卵巢癌类器官培养模型中会促进肿瘤生长，并通过多种信号通路介导耐药性。这为阐明卵巢癌耐药机制和开发靶向治疗提供了可靠的研究模型。
