SENTINEL study · Serotonin at the epigenetic nexus of tumorigenesis in Epstein Barr lymphoma

The rising global incidence of Epstein-Barr virus (EBV)-related cancers highlights the urgent need to explore the mechanisms driving their pathogenesis. Many of these tumours are highly aggressive, with poor patient outcomes. The viral latent membrane protein-1 (LMP1) drives oncogenesis through poorly understood epigenetic mechanisms. Serotonin, which influences viral replication, has recently been linked to the regulation of gene expression in cancers via serotonylation, a newly discovered histone modification. However, whether serotonylation influences LMP1-driven oncogenesis remains unknown. Cancer-altered tryptophan metabolism reduces serotonin levels, partly through the recruitment of indoleamine 2,3-dioxygenase-1 (IDO1)-expressing macrophages that promote cancer progression, but it is unclear if viral factors are involved in their recruitment. Additionally, EBV binds to platelets, the body's richest serotonin source, though the significance of this interaction is also unknown. SENTINEL will adopt an interdisciplinary approach, integrating virology, epigenetics, immunology, and platelet biology to shed new insights into EBV driven cancer development. The fellowship comprises three research objectives (work packages WP1-3): WP1 will identify cellular and viral genes influenced by serotonylation, WP2 will examine EBV’s role in recruiting IDO1+ macrophages, and WP3 will investigate how platelets and platelet-derived serotonin regulate EBV’s life cycle. This research is a collaboration between leading experts in virology, epigenetics, immunology, and cancer biology, providing the Postdoctoral Fellow with a unique set of training opportunities in preparation for an independent research career. In uncovering novel tumorigenic mechanisms, the project is expected to pave the way for the development of new targeted therapies that could improve patient outcomes.