Testicular germ cell tumor (GCT) is the most common type of malignancy in young males. Patients with nonseminomatous GCT still have poor prognosis. To identify new therapeutic targets, we generated patient-derived cells (PDCs) and their xenograft (PDCX) models from 3 distinct GCT patients' specimens. The pathological features of GCT PDCs and PDCX tumors recapitulated those of nonseminomatous components exhibiting in the corresponding patients’ specimens. Notably, stemness-related markers and hypoxia-related genes, including hypoxia inducible factor 1α (HIF1A) and neuritin 1 (NRN1), were abundantly expressed in three-dimensional spheroid cultures of GCT PDCs. We identified functional HIF1α response elements in the NRN1 promoter and defined that their transcriptional activities were substantially activated by hypoxia. HIF1α inhibition by siRNAs or an inhibitor, 2-methoxyestradiol, significantly suppressed NRN1 expression and decreased the in vitro and in vivo growth of PDC spheroids. Moreover, NRN1 knockdown efficiently suppressed PDC proliferation. These results suggest that HIF1α and NRN1 are potential diagnostic and therapeutic targets, and that 2-methoxyestradiol could be applied to clinical management of GCT. Overall, our GCT PDC and PDCX models would be useful as preclinical models for precision medicine targeting each patient.

睾丸生殖细胞肿瘤（GCT）是年轻男性中最常见的恶性肿瘤类型。非精原细胞性GCT患者的预后仍然较差。为了确定新的治疗靶标，我们从3个不同的GCT患者标本中生成了患者来源的细胞（PDC）及其异种移植（PDCX）模型。GCT PDC和PDCX肿瘤的病理特征概括了在相应患者标本中表现出的非精原细胞成分。值得注意的是，在GCT PDC的三维球体培养物中大量表达了与干性相关的标记和与缺氧相关的基因，包括缺氧诱导因子1α（HIF1A）和神经氨酸1（NRN1）。我们在NRN1中鉴定了功能性HIF1α反应元件启动子，并定义其转录活性基本上被缺氧激活。siRNA或抑制剂2-甲氧基雌二醇对HIF1α的抑制作用显着抑制了NRN1的表达，并降低了PDC球体的体外和体内生长。此外，NRN1组合式有效抑制PDC增殖。这些结果表明，HIF1α和NRN1是潜在的诊断和治疗靶标，并且2-甲氧基雌二醇可用于GCT的临床管理。总体而言，我们的GCT PDC和PDCX模型可用作针对每个患者的精准医学的临床前模型。