The human microbiome is a complex, multi-kingdom community that exists in symbiotic relationships with the human host at multiple body sites. Microbiome communities influence the development, progression, metastasis formation, and treatment response of several cancer types. While causal evidence is scarce, enhanced molecular understanding of such cancer-modulating microbial interactions and their impact on cancer treatment is considered of major scientific importance and clinical relevance. By combining 3D cell culture technology, mutational signature analysis and DNA damage response profiling, we study the impact of the microbiome on human tumour microevolution. We are particularly interested in the microbiome-associated mutagenic mechanisms that boost cancer progression. We develop an integrated framework that allows patient stratification, i.e. grouping of patients based on cancer risk and response to therapy. Additionally, these investigations will reveal novel human DNA damage response pathways involved in cancer progression. Our ultimate goal is to develop microbiome-associated biomarkers from non-malignant patients before tumors develop, thereby transforming therapeutic strategies from reactive to predictive.