Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Department of Ophthalmology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Sci Rep. 2018 Oct 23;8(1):15664. doi: 10.1038/s41598-018-34037-y.
Persistent or recurrent retinoblastoma (RB) is associated with the presence of vitreous or/and subretinal seeds in advanced RB and represents a major cause of therapeutic failure. This necessitates the development of novel therapies and thus requires a model of advanced RB for testing candidate therapeutics. To this aim, we established and characterized a three-dimensional, self-organizing organoid model derived from chemotherapy-naïve tumors. The responses of organoids to drugs were determined and compared to relate organoid model to advanced RB, in terms of drug sensitivities. We found that organoids had histological features resembling retinal tumors and seeds and retained DNA copy-number alterations as well as gene and protein expression of the parental tissue. Cone signal circuitry (M/L cells) and glial tumor microenvironment (GFAP cells) were primarily present in organoids. Topotecan alone or the combined drug regimen of topotecan and melphalan effectively targeted proliferative tumor cones (RXRγ Ki67) in organoids after 24-h drug exposure, blocking mitotic entry. In contrast, methotrexate showed the least efficacy against tumor cells. The drug responses of organoids were consistent with those of tumor cells in advanced disease. Patient-derived organoids enable the creation of a faithful model to use in examining novel therapeutics for RB.
持续性或复发性视网膜母细胞瘤 (RB) 与晚期 RB 中玻璃体内或/和视网膜下种子的存在相关，是治疗失败的主要原因。这需要开发新的治疗方法，因此需要建立晚期 RB 的模型来测试候选治疗方法。为此，我们建立并鉴定了一种源自化疗初治肿瘤的三维自组织类器官模型。我们测定了类器官对药物的反应，并根据药物敏感性将类器官模型与晚期 RB 进行了比较。我们发现，类器官具有类似于视网膜肿瘤和种子的组织学特征，并保留了亲本组织的 DNA 拷贝数改变以及基因和蛋白表达。类器官中主要存在视锥信号通路（M/L 细胞）和神经胶质肿瘤微环境（GFAP 细胞）。单独使用拓扑替康或拓扑替康和氨甲蝶呤联合药物方案在药物暴露 24 小时后可有效靶向类器官中的增殖性肿瘤锥体细胞（RXRγ Ki67），阻止有丝分裂进入。相比之下，甲氨蝶呤对肿瘤细胞的疗效最差。类器官的药物反应与晚期疾病中肿瘤细胞的反应一致。患者来源的类器官使创建忠实的模型成为可能，可用于研究 RB 的新型治疗方法。
