Group Marinoni, Perren, Sadowski   Cancer is a dynamic disease; genetic and epigenetic alterations drive intra-tumoral cell heterogeneity, resulting in the selection of aggressive cell populations capable of driving progression and ultimately metastasis. Pancreatic neuroendocrine tumours (PanNETs) are tumours that arise from the islets of Langerhans. They exhibit intra-tumoral cell heterogeneity, but it is unclear how this evolves during tumour development and how it contributes to progression. Our previous data suggest that epigenetic changes are the major drivers of progression and cell heterogeneity in PanNETs. By integrating epigenetic and transcriptomic profiles, we found that cell dedifferentiation and metabolic changes characterise the progression from small PanNETs to more advanced ones. We are currently investigating the evolution of intra-tumoral heterogeneity of PanNETs through space and time. Specific cell subpopulations identified as driving progression could then be targeted to stop metastasis formation. The identification of targetable pathways that impair metastasis formation will provide a rationale for new treatments.