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Modelling DNA methylation in the systemic progression of cancer

癌症全身进展中的 DNA 甲基化建模

基本信息

批准号：
392961754
负责人：
Professor Dr. Michael Rehli
金额：
--
依托单位：
Klinik und Poliklinik für Innere Medizin III
依托单位国家：
德国
项目类别：
Research Units
财政年份：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2021-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/392961754?language=en
关键词：
Modelling DNA methylation systemic progression

项目摘要

DNA methylation is a heritable epigenetic mechanism that is frequently altered in cancer and that shows significant intratumoural heterogeneity. It also integrates transcriptional and metabolic signals, and may thus stabilize/support metastatic transcriptional programs complementing the effects of genetic alterations. The BalbNeuT mouse model studied by our consortium lacks genetic evidence for metastatic driver mutations. However, it shows marked epigenetic differences between primary tumours and metastasis. It is therefore ideally suited to model methylation progression addressing key questions regarding the impact of epigenetic alterations on metastatic progression. In the first funding period the projects A2 (Spang) and A4 (Rehli) collaborated intensively to study methylation progression in the context of the BalbNeuT mouse model. We have monitored DNA methylation during systemic progression, have identified multiple distinct patterns of methylation progression, and have developed a new type of dynamic cross sectional models that allows for the joint analysis of methylation timing and the causal relations between methylation and dissemination.Joining forces and building on these results, we now propose to develop a novel type of epigenetic progression models, that include early lesions in addition to full grown primary tumours and lung metastasis, fine tune them on a representative set of 25 promoter regions that recurrently show methylation progression, and validate the model using CRISPR/Cas9 mediated gene silencing assays. Moreover, we will use longitudinal liquid biopsies to search for progressed methylation early in systemic progression.

DNA甲基化是一种可遗传的表观遗传机制，在癌症中经常改变，并显示出显著的肿瘤内异质性。它还整合了转录和代谢信号，因此可以稳定/支持补充遗传改变影响的转移性转录程序。我们联盟研究的BalbNeuT小鼠模型缺乏转移驱动突变的遗传学证据。然而，它显示出原发肿瘤和转移瘤之间明显的表观遗传学差异。因此，它非常适合于模拟甲基化进程，解决有关表观遗传改变对转移进程的影响的关键问题。在第一个资助期，A2(Spang)和A4(Rehli)项目密切合作，在BalbNeuT小鼠模型的背景下研究甲基化进程。我们监测了系统进展中的DNA甲基化，确定了多种不同的甲基化进展模式，并开发了一种新型的动态横截面模型，允许联合分析甲基化时机以及甲基化和传播之间的因果关系。结合这些力量并基于这些结果，我们现在建议开发一种新型的表观遗传进展模型，包括除完全生长的原发肿瘤和肺转移之外的早期病变，在一组具有代表性的25个重复显示甲基化进展的启动子区域上对它们进行微调，并使用CRISPR/Cas9介导的基因沉默分析来验证该模型。此外，我们将使用纵向液体活检来寻找系统性进展的早期进展的甲基化。