Evolution of genetic & epigenetic aberrations during malignant progression of breast cancerand the impact of the local environment

遗传学的进化

• 批准号: 257888998
• 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: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/257888998?language=en
• 关键词: Evolution; genetic; epigenetic; aberrations; during

Aberrant changes in DNA methylation are frequent and early events during malignant transformation that are thought to play an important role in disease initiation and manifestation. However, the mechanisms driving epigenetic deregulation remain largely obscure. Some epigenetic changes observed in cancer are subject to a tumour cell-intrinsic control while others may be caused by “environmental” factors, including stroma- or immune cell interactions within the evolving tumour, but the latter issue has rarely been addressed systematically. This project ultimately aims at dissecting the contribution of genetic and epigenetic mechanisms to tumour progression in general and to establish an impact of the tumour microenvironment, in particular of innate immune cells (trophic and pro-tumoural macrophages), on the evolution of cancer cell genomes and epigenomes during malignant progression. To this end, we plan to study the inbred BalbNeuT mouse model of breast cancer, which closely resembles human disease. In close collaboration with Christoph Klein and Rainer Spang, we will track and analyse general cancer-related (epi)genetic changes during metastatic progression and compare how “normal” or altered microenvironment influence the evolution and dissemination of tumour cells. The study will (I.) uncover relevant epigenetic signatures that are associated with tumour progression, (II.) provide insights into mechanisms shaping cancer cell epigenomes and (III.) shed light on the impact of innate immune cells on evolving cancer cell genomes and epigenomes.

DNA 甲基化的异常变化是恶性转化过程中常见的早期事件，被认为在疾病的发生和表现中发挥着重要作用。然而，驱动表观遗传失调的机制在很大程度上仍然不清楚。在癌症中观察到的一些表观遗传变化受到肿瘤细胞内在控制，而另一些则可能是由“环境”因素引起的，包括不断发展的肿瘤内的基质细胞或免疫细胞相互作用，但后一个问题很少得到系统解决。该项目的最终目标是剖析遗传和表观遗传机制对肿瘤进展的总体贡献，并确定肿瘤微环境，特别是先天免疫细胞（营养性和促肿瘤巨噬细胞）对恶性进展过程中癌细胞基因组和表观基因组进化的影响。为此，我们计划研究乳腺癌近交 BalbNeuT 小鼠模型，该模型与人类疾病非常相似。通过与 Christoph Klein 和 Rainer Spang 的密切合作，我们将跟踪和分析转移进展过程中与癌症相关的（表观）遗传变化，并比较“正常”或改变的微环境如何影响肿瘤细胞的进化和传播。该研究将（I.）揭示与肿瘤进展相关的相关表观遗传特征，（II.）提供对塑造癌细胞表观基因组的机制的见解，以及（III.）揭示先天免疫细胞对不断进化的癌细胞基因组和表观基因组的影响。