Identification of targetable pathways of prognostic relevance involved in the biology of atypical teratoid/rhabdoid tumors (AT/RT).

鉴定与非典型畸胎瘤/横纹肌样肿瘤 (AT/RT) 生物学相关的预后相关的靶向途径。

• 批准号: 258565917
• 负责人: Professor Dr. Martin Hasselblatt
• 金额: --
• 依托单位: Institut für Neuropathologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/258565917?language=en
• 关键词: Identification; targetable; pathways; prognostic; relevance

Atypical teratoid/rhabdoid tumors (AT/RT) are malignant brain tumors mainly affecting young children. Despite aggressive therapeutic approaches, the prognosis of AT/RT remains dismal. Genetic alterations resulting in functional loss of SMARCB1 or SMARCA4 are characteristic. These genes are members of the evolutionarily highly conserved ATP-dependent SWI/SNF chromatin remodeling complex, which plays a key role in the epigenetic regulation of cell proliferation and differentiation. Little is known, however, on targetable downstream pathways involved in the oncogenic effects of SMARCB1 inactivation or SMARCA4 inactivation. We thus assume that investigation of downstream signaling pathways is essential for a better understanding of the molecular pathogenesis of AT/RT. The majority of AT/RT shows SMARCB1 deficiency. Based on our previous results in a fly model of SMARCB1-deficiency, we will therefore further investigate the role of identified candidate genes in the biology of AT/RT. Specifically, we are interested to learn why the function of the genes merlin, kibra and expanded is essential for the phenotype associated with knockdown of snr1, the fly homolog of SMARCB1. To this end, we will investigate signaling pathways using reporter assays and gene expression profiling in Drosophila melanogaster and confirm the role of identified pathways in human SMARCB1-deficient rhabdoid tumor cell lines. Some AT/RT show retained SMARCB1 function, but genetic alterations causing functional loss of SMARCA4. We therefore also aim to identify pathways involved in the detrimental effects of SMARCA4 deficiency. To achieve this goal, we will establish a fly model of SMARCA4 deficiency using brm knockdown flies. Using a modifier screen and more than 1000 fly strains expressing various siRNA constructs, we will identify those genes functionally involved in the phenotype associated with brm knockdown. The functional role of identified candidate genes will be confirmed in human SMARCA4-deficient human rhabdoid tumor cell lines by exploring the effect of siRNA silencing and pharmacological inhibition on tumor cell proliferation and migration.After confirming the importance of identified genes and pathways in a mouse xenograft model as well as examining the consequences of their expression on prognosis and therapy response in human AT/RT samples obtained through the European Rhabdoid Tumor Registry EU-RHAB, we will be able to provide novel avenues for targeted therapies. In the long-term, our goal is to provide the prerequisites for a better treatment of children with AT/RT. Our results might also contribute to better treatment of other tumor entities showing functional loss of SMARCB1 or SMARCA4.

非典型畸胎样/横纹肌样肿瘤（AT/RT）是主要影响幼儿的恶性脑肿瘤。尽管积极的治疗方法，AT/RT的预后仍然令人沮丧。导致SMARCB 1或SMARCA 4功能丧失的遗传改变是特征性的。这些基因是进化上高度保守的ATP依赖性SWI/SNF染色质重塑复合物的成员，该复合物在细胞增殖和分化的表观遗传调控中起关键作用。然而，对SMARCB 1失活或SMARCA 4失活的致癌作用所涉及的靶向下游通路知之甚少。因此，我们认为，下游信号通路的调查是必不可少的更好地了解AT/RT的分子发病机制。大多数AT/RT显示SMARCB 1缺陷。基于我们以前的结果，在一个苍蝇模型SMARCB 1缺陷，因此，我们将进一步研究的作用，确定候选基因的生物学AT/RT。具体来说，我们有兴趣了解为什么基因梅林，kibra和扩展的功能是必不可少的表型与敲低snr 1，苍蝇同源SMARCB 1。为此，我们将研究信号通路，使用报告基因分析和基因表达谱在果蝇和确认的作用，在人类SMARCB 1缺陷横纹肌样肿瘤细胞系的途径。一些AT/RT显示保留了SMARCB 1功能，但遗传改变导致SMARCA 4功能丧失。因此，我们的目标也是确定参与SMARCA 4缺陷的有害影响的途径。为了实现这一目标，我们将使用brm敲低果蝇建立SMARCA 4缺陷的果蝇模型。使用修饰筛选和超过1000个表达各种siRNA构建体的果蝇品系，我们将鉴定那些在功能上参与与brm敲低相关的表型的基因。通过探索siRNA沉默和药理学抑制对肿瘤细胞增殖和迁移的影响，将在人SMARCA 4缺陷型人横纹肌样肿瘤细胞系中证实所鉴定的候选基因的功能作用。通过欧洲横纹肌样肿瘤登记处EU-RHAB获得的RT样本，我们将能够为靶向治疗提供新的途径。从长远来看，我们的目标是为更好地治疗AT/RT儿童提供先决条件。我们的研究结果也可能有助于更好地治疗显示SMARCB 1或SMARCA 4功能丧失的其他肿瘤实体。

项目成果

ATRT-34. TARGETING PRIMARY CILIOGENESIS IN ATYPICAL TERATOID/RHABDOID TUMORS

ATRT-34 靶向非典型畸胎瘤/横纹肌样肿瘤的原发纤毛发生

• DOI: 10.1093/neuonc/noy059.031
• 发表时间: 2018
• 期刊: Neuro-Oncology
• 影响因子: 15.9
• 作者: Blümel L;Kerl K;Berlandi J;Thiel K;Tegeder I;Jeibmann A;Picard D;Langini M;Stühler K;Meyer F;Malzkorn B;Liebau MC;Johann PD;Erkek S;Kool K;Pfister SM;Frühwald MC;Borkhardt A;Reifenberger G;Hasselblatt M;Remke M
• 通讯作者: Remke M

Functional relevance of genes predicted to be affected by epigenetic alterations in atypical teratoid/rhabdoid tumors

预测受非典型畸胎瘤/横纹肌样肿瘤表观遗传改变影响的基因的功能相关性

• DOI: 10.1007/s11060-018-03018-6
• 发表时间: 2019
• 期刊: Journal of Neuro-Oncology
• 影响因子: 3.9
• 作者: Tegeder;Isabel;Katharina;Johann;Pascal D;Berlandi;Johannes;Thatikonda;Frühwald;Michael C;Marcel;Jeibmann;Astrid;Hasselblatt;Martin
• 通讯作者: Martin

ATRT-05. USING DROSOPHILA TO EXPLORE THE FUNCTIONAL RELEVANCE OF GENES AFFECTED BY EPIGENETIC ALTERATIONS IN ATYPICAL TERATOID/RHABDOID TUMORS (AT/RT)

ATRT-05 使用果蝇探索非典型畸胎瘤/横纹肌样肿瘤 (AT/RT) 中受表观遗传改变影响的基因的功能相关性

• DOI: 10.1093/neuonc/noy059.004
• 发表时间: 2018
• 期刊: Neuro-Oncology
• 影响因子: 15.9
• 作者: Tegeder I;Thiel K;Berlandi J;Johann P;Erkek S;Jeibmann A;Hasselblatt
• 通讯作者: Hasselblatt