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

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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.