Modelling DNA methylation in the systemic progression of cancer

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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.