Role of myeloid cells and leukotriene signalling in Uveal Melanoma progression

Uveal melanoma (UM) is the most common and fatal primary intraocular malignancy in adults. Most UM patients carry activating mutations in Gαq or Gα11, alpha subunits of trimeric G-proteins associated with cysteinyl leukotriene receptors (CYSLTRs). To investigate the involvement of leukotrienes in activating CYSLTRs and their ability to induce YAP signalling, we generated four genetically distinct zebrafish uveal melanoma models and analysed the role of different cells in leukotriene production. Treatment of primary UM cells and zebrafish UM explants with leukotrieneD4 (LTD4) induced the overexpression of PTK2/FAK, a positive activator of YAP signalling, and upregulation of YAP targets, while co-treatment with a CYSLTR2 inhibitor prevented LTD4-mediated YAP activation. Single-cell transcriptomic analysis of the zebrafish UM models revealed neutrophils as the major producers of leukotrienes and provided information on the YAP transcriptional program activated by leukotrienes. In support of the role of neutrophils in UM progression, we found that transplantation of UM cells in zebrafish induced reactive neutrophilia and neutrophil infiltration of the transplanted tumours, while neutrophil ablation reduces tumour growth. We suggest that neutrophils contribute to UM development by producing LTD4, which interacts with CYSLTR2 and facilitated by the activated status of mutant Gα11, promotes YAP signalling and UM progression.