The occurrence of intracranial rhabdoid tumours in mice depends on temporal control of Smarcb1 inactivation.
The occurrence of intracranial rhabdoid tumours in mice depends on temporal control of Smarcb1 inactivation.
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DOI：
10.1038/ncomms10421
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发表时间：
2016-01-28
影响因子：
16.6
通讯作者：
Bourdeaut F
中科院分区：
文献类型：
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作者：
Han ZY;Richer W;Fréneaux P;Chauvin C;Lucchesi C;Guillemot D;Grison C;Lequin D;Pierron G;Masliah-Planchon J;Nicolas A;Ranchère-Vince D;Varlet P;Puget S;Janoueix-Lerosey I;Ayrault O;Surdez D;Delattre O;Bourdeaut F
横纹肌样瘤（RT）是婴儿期的高度侵袭性肿瘤，通常位于中枢神经系统（CNS），在中枢神经系统中，它们被称为非典型畸胎瘤/横纹肌样瘤（AT/RT），其特征在于SMARCB 1肿瘤抑制基因的双等位基因失活。在这项研究中，通过时间控制Smarcb 1flox/flox; Rosa 26-CreERT 2小鼠注射他莫昔芬，我们探讨了与Smarcb 1失活在不同发育阶段的表型。在E6前、出生时或2月龄时注射分别概括了先前描述的表型，包括胚胎致死性、肝毒性或T细胞淋巴瘤的发展。E6和E10之间的注射导致高转移率肿瘤，主要是颅内肿瘤，延迟时间较短（中位数：3个月）。这些肿瘤表现出与人类AT/RT一致的解剖学、形态学和基因表达谱。此外，肿瘤的种内和种间比较显示，人类和小鼠RT可以分为不同的实体，这可能强调了RT细胞起源的多样性。 SMARCB 1失活在人类非典型畸胎样/横纹肌样肿瘤中普遍存在，但缺乏准确模拟人类疾病的小鼠模型。在这里，作者表明，与先前报道的模型相比，小鼠E6和E10之间SMARCB 1的失活导致肿瘤更好地再现了人类表型。
Rhabdoid tumours (RTs) are highly aggressive tumours of infancy, frequently localized in the central nervous system (CNS) where they are termed atypical teratoid/rhabdoid tumours (AT/RTs) and characterized by bi-allelic inactivation of the SMARCB1 tumour suppressor gene. In this study, by temporal control of tamoxifen injection in Smarcb1flox/flox;Rosa26-CreERT2 mice, we explore the phenotypes associated with Smarcb1 inactivation at different developmental stages. Injection before E6, at birth or at 2 months of age recapitulates previously described phenotypes including embryonic lethality, hepatic toxicity or development of T-cell lymphomas, respectively. Injection between E6 and E10 leads to high penetrance tumours, mainly intra-cranial, with short delays (median: 3 months). These tumours demonstrate anatomical, morphological and gene expression profiles consistent with those of human AT/RTs. Moreover, intra- and inter-species comparisons of tumours reveal that human and mouse RTs can be split into different entities that may underline the variety of RT cells of origin. SMARCB1 inactivation is prevalent in human atypical teratoid/rhabdoid tumours but a mouse model that accurately phenocopies the human disease is lacking. Here, the authors show that inactivation of SMARCB1 between E6 and E10 in mice results in tumours that better recapitulate the human phenotype, compared to previously reported models.