Corresponding authors: Jennifer A. Chan, MD, Department of Pathology & Laboratory Medicine, University of Calgary, HRIC 2A25, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1.
Neuro Oncol. 2014 Jan;16(1):62-71. doi: 10.1093/neuonc/not162. Epub 2013 Dec 4.
Embryonal tumor with multilayered rosettes (ETMR) is an aggressive central nervous system primitive neuroectodermal tumor (CNS-PNET) variant. ETMRs have distinctive histology, amplification of the chromosome 19 microRNA cluster (C19MC) at chr19q13.41-42, expression of the RNA binding protein Lin28, and dismal prognosis. Functional and therapeutic studies of ETMR have been limited by a lack of model systems.
We have established a first cell line, BT183, from a case of ETMR and characterized its molecular and cellular features. LIN28 knockdown was performed in BT183 to examine the potential role of Lin28 in regulating signaling pathway gene expression in ETMR. Cell line findings were corroborated with immunohistochemical studies in ETMR tissues. A drug screen of 73 compounds was performed to identify potential therapeutic targets.
The BT183 line maintains C19MC amplification, expresses C19MC-encoded microRNAs, and is tumor initiating. ETMRs, including BT183, have high LIN28 expression and low let-7 miRNA expression, and show evidence of mTOR pathway activation. LIN28 knockdown increases let-7 expression and decreases expression of IGF/PI3K/mTOR pathway components. Pharmacologic inhibition of the mTOR pathway reduces BT183 cell viability.
BT183 retains key genetic and histologic features of ETMR. In ETMR, Lin28 is not only a diagnostic marker but also a regulator of genes involved in growth and metabolism. Our findings indicate that inhibitors of the IGF/PI3K/mTOR pathway may be promising novel therapies for these fatal embryonal tumors. As the first patient-derived cell line of these rare tumors, BT183 is an important, unique reagent for investigating ETMR biology and therapeutics.
具有多层玫瑰花结的胚胎性肿瘤（ETMR）是一种侵袭性中枢神经系统原始神经外胚层肿瘤（CNS-PNET）变体。ETMR 具有独特的组织学特征，在染色体 19q13.41-42 处存在 19 号染色体微小 RNA 簇（C19MC）的扩增，表达 RNA 结合蛋白 Lin28，预后较差。由于缺乏模型系统，ETMR 的功能和治疗研究受到限制。
我们从 ETMR 病例中建立了第一个细胞系 BT183，并对其分子和细胞特征进行了表征。在 BT183 中进行 LIN28 敲低，以研究 Lin28 在调节 ETMR 信号通路基因表达中的潜在作用。在 ETMR 组织中进行免疫组织化学研究以验证细胞系发现。对 73 种化合物进行药物筛选，以确定潜在的治疗靶点。
BT183 系保持 C19MC 扩增，表达 C19MC 编码的 microRNAs，并具有肿瘤起始能力。ETMR，包括 BT183，具有高 LIN28 表达和低 let-7 miRNA 表达，并显示 mTOR 途径激活的证据。LIN28 敲低增加了 let-7 的表达并降低了 IGF/PI3K/mTOR 途径成分的表达。mTOR 途径的药理学抑制降低了 BT183 细胞的活力。
BT183 保留了 ETMR 的关键遗传和组织学特征。在 ETMR 中，Lin28 不仅是诊断标志物，还是参与生长和代谢的基因的调节剂。我们的研究结果表明，IGF/PI3K/mTOR 途径抑制剂可能是这些致命的胚胎性肿瘤有前途的新型治疗方法。作为这些罕见肿瘤的第一个患者来源的细胞系，BT183 是研究 ETMR 生物学和治疗学的重要独特试剂。
