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

DNA甲基化的异常变化是恶性转化过程中经常发生的早期事件，被认为在疾病的发生和表现中起重要作用。然而，驱动表观遗传放松管制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肿瘤细胞的内在控制，而另一些可能由“环境”因素引起，包括肿瘤进化中的基质或免疫细胞相互作用，但后者的问题很少得到系统的解决。该项目的最终目的是剖析遗传和表观遗传机制对肿瘤进展的贡献，并确定肿瘤微环境，特别是先天免疫细胞（营养和促肿瘤巨噬细胞）在恶性进展过程中对癌细胞基因组和表观基因组进化的影响。为此，我们计划研究近交BalbNeuT小鼠乳腺癌模型，该模型与人类疾病非常相似。在与Christoph Klein和Rainer Spang的密切合作中，我们将跟踪和分析转移过程中的一般癌症相关（epi）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(1)揭示与肿瘤进展相关的表观遗传特征，(2)为形成癌细胞表观基因组的机制提供见解，(3)阐明先天免疫细胞对进化的癌细胞基因组和表观基因组的影响。

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.