Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Int J Mol Sci. 2023 Mar 7;24(6):5091. doi: 10.3390/ijms24065091.
Peritoneal implantation and lymph node metastasis have different driving mechanisms in ovarian cancer. Elucidating the underlying mechanism of lymph node metastasis is important for treatment outcomes. A new cell line, FDOVL, was established from a metastatic lymph node of a patient with primary platinum-resistant ovarian cancer and was then characterized. The effect of -p.C702fs mutation and NOTCH1 inhibitor on migration was evaluated in vitro and in vivo. Ten paired primary sites and metastatic lymph nodes were analyzed by RNA sequencing. The FDOVL cell line with serious karyotype abnormalities could be stably passaged and could be used to generated xenografts. -p.C702fs mutation was found exclusively in the FDOVL cell line and the metastatic lymph node. The mutation promoted migration and invasion in cell and animal models, and these effects were markedly repressed by the NOTCH inhibitor LY3039478. RNA sequencing confirmed CSF3 as the downstream effector of mutation. Furthermore, the mutation was significantly more common in metastatic lymph nodes than in other peritoneal metastases in 10 paired samples (60% vs. 20%). The study revealed that NOTCH1 mutation is probably a driver of lymph node metastasis in ovarian cancer, which offers new ideas for the treatment of ovarian cancer lymph node metastasis with NOTCH inhibitors.
腹膜种植和淋巴结转移在卵巢癌中有不同的驱动机制。阐明淋巴结转移的潜在机制对于治疗结果至关重要。本研究从铂耐药原发性卵巢癌患者的转移性淋巴结中建立了一个新的细胞系 FDOVL，并对其进行了特征描述。体外和体内实验评估了 -p.C702fs 突变和 NOTCH1 抑制剂对迁移的影响。对 10 对原发性肿瘤和转移性淋巴结进行了 RNA 测序分析。具有严重染色体异常的 FDOVL 细胞系可稳定传代，并可用于生成异种移植物。-p.C702fs 突变仅在 FDOVL 细胞系和转移性淋巴结中发现。该突变促进了细胞和动物模型中的迁移和侵袭，而 NOTCH 抑制剂 LY3039478 则显著抑制了这些效应。RNA 测序证实 CSF3 是突变的下游效应物。此外，在 10 对配对样本中，该突变在转移性淋巴结中的发生率明显高于其他腹膜转移（60% vs. 20%）。该研究表明，NOTCH1 突变可能是卵巢癌淋巴结转移的驱动因素，为 NOTCH 抑制剂治疗卵巢癌淋巴结转移提供了新的思路。
