Melanoma innervation is associated with cancer progression in a zebrafish xenograft model

The peripheral nervous system has a key role in regulating tumour biology in different types of cancer. Here, by modelling aggressive melanoma in larval zebrafish xenografts, we highlight the dynamics of tumour innervation in the tumour microenvironment (TME). Axonogenesis and dendritogenesis are detected in the motoneurons surrounding the melanoma niche and neurogenesis is observed in the nearby population of the enteric nervous system. We also demonstrate the crucial role of catecholamines in promoting melanoma progression, supporting in vivo cancer cell dissemination and invasion. This zebrafish model will allow to uncover neural markers associated with melanoma progression to help in the design of innovative anti-neurogenic therapies targeting specifically the neuronal signals that regulate melanoma progression. Graphical abstract Highlights Transplantation of human melanoma cells in 3 dpf zebrafish swim bladder allows the development of aggressive melanoma, which cells invade the surrounding organs and migrate over distant locations. The presence of melanoma cells in the larval zebrafish induces morphological changes in the motoneurons inside the tumour niche, including increased axon length and dendritic arborization. The invasion of melanoma cells in the larval intestine promotes neurogenesis of enteric neurons. Transplanted melanoma cells display direct contact with enteric neurons in the intestinal region and migrate along axons to escape from the primary cancer mass, as a mechanism similar to vessel co-option during metastatic dissemination. Catecholamines promote melanoma cell migration and invasion in the zebrafish, modelling melanoma progression.