El Nagar Salsabiel, Zindy Frederique, Moens Charlotte, Martin Luc, Plassard Damien, Roussel Martine F, Lamonerie Thomas, Billon Nathalie
Université Côte d'Azur, CNRS, Inserm, iBV, Nice, France.
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Biochem Biophys Res Commun. 2018 Feb 5;496(2):568-574. doi: 10.1016/j.bbrc.2017.11.192. Epub 2018 Jan 12.
Choroid plexus carcinomas (CPCs) are highly malignant brain tumours predominantly found in children and associated to poor prognosis. Improved therapy for these cancers would benefit from the generation of animal models. Here we have created a novel mouse CPC model by expressing a stabilised form of c-Myc (MycT58A) and inactivating Trp53 in the choroid plexus of newborn mice. This induced aberrant proliferation of choroid plexus epithelial cells, leading to aggressive tumour development and death within 150 days. Choroid plexus tumours occurred with a complete penetrance in all brain ventricles, with prevalence in the lateral and fourth ventricles. Histological and cellular analysis indicated that these tumours were CPCs resembling their human counterparts. Comparison of gene expression profiles of CPCs and non-neoplastic tissues revealed profound alterations in cell cycle regulation and DNA damage responses, suggesting that dysregulation of cell division and DNA checkpoint pathways may represent key vulnerabilities. This novel animal model of CPC provides an invaluable tool to elucidate the mechanism of CPC formation and to develop successful therapies against this devastating paediatric cancer.
脉络丛癌（CPCs）是一种高度恶性的脑肿瘤，主要发生于儿童，预后较差。建立动物模型将有助于改善这些癌症的治疗方法。在此，我们通过在新生小鼠的脉络丛中表达一种稳定形式的c-Myc（MycT58A）并使Trp53失活，创建了一种新型小鼠CPC模型。这导致脉络丛上皮细胞异常增殖，在150天内引发侵袭性肿瘤发展并导致死亡。脉络丛肿瘤在所有脑室中均完全显性发生，在侧脑室和第四脑室中更为常见。组织学和细胞分析表明，这些肿瘤为CPCs，与人类同类肿瘤相似。CPCs与非肿瘤组织的基因表达谱比较显示，细胞周期调控和DNA损伤反应发生了深刻改变，这表明细胞分裂和DNA检查点途径的失调可能是关键的薄弱环节。这种新型CPC动物模型为阐明CPC形成机制以及开发针对这种毁灭性儿科癌症的成功治疗方法提供了宝贵工具。
