Modelling DNA methylation in the systemic progression of cancer

癌症全身进展中的 DNA 甲基化建模

• 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

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，在癌症中经常发生改变，并表现出显着的肿瘤内异质性。它还整合转录和代谢信号，因此可以稳定/支持转移转录程序，补充遗传改变的影响。我们联盟研究的 BalbNeuT 小鼠模型缺乏转移性驱动突变的遗传证据。然而，它显示出原发肿瘤和转移肿瘤之间显着的表观遗传差异。因此，它非常适合模拟甲基化进展，解决有关表观遗传改变对转移进展影响的关键问题。在第一个资助期间，项目 A2 (Spang) 和 A4 (Rehli) 密切合作，研究 BalbNeuT 小鼠模型背景下的甲基化进展。我们监测了全身进展过程中的 DNA 甲基化，确定了多种不同的甲基化进展模式，并开发了一种新型动态横截面模型，可以联合分析甲基化时间以及甲基化与传播之间的因果关系。在这些结果的基础上，联合力量，我们现在建议开发一种新型表观遗传进展模型，除了完全生长的原发肿瘤和肺外，还包括早期病变 转移，在一组代表性的 25 个启动子区域上进行微调，这些启动子区域反复显示甲基化进程，并使用 CRISPR/Cas9 介导的基因沉默测定来验证模型。此外，我们将使用纵向液体活检来寻找全身进展早期进展的甲基化。