Mast cells act as pro-angiogenic and pro-tumorigenic players in pituitary gonadotroph tumors

Background: The tumor microenvironment (TME) represents a promising avenue to understand gonadotroph tumors and develop therapeutic tools. Here, we aimed to gain insight into the tumorigenesis mechanisms driven by the gonadotoph TME. Methods: Single-cell and spatial-omics were combined with histological analysis. Mice engrafted with tumor cells were used for functional validation. Results: using single-cell and spatial transcriptomic data from gonadotroph tumors and normal tissues, we identified mast cells in the microenvironment of gonadotroph tumors and confirmed their physical and functional interaction with endothelial cells. Quantification of mast cells in 40 patients suggested their pro-tumoral role as tumors relapsing after surgery harbored more mast cells. More interestingly, the distribution of mast cells was associated with the presence of a higher number of blood vessels, with an increased microvessel density (MVD), and with blood vessels with thicker walls. Ligand-receptor network analysis highlighted VEGFA as a modulator of mast/endothelial cell communication, a result confirmed by the identification of intratumoral mast cells expressing VEGFA in mouse and human gonadotroph tumors. Finally, using mice engrafted with gonadotroph tumor cells, we demonstrated that the depletion of mast cells reduces tumor volume through increased apoptosis. These observations were associated with increased hemorrhagic areas and a significant reduction of the number of blood vessels and MVD as evidenced in human gonadotroph tumors. Conclusion: we demonstrate that mast cells represent a new actor of the gonadotroph TME, and highlight their pro-angiogenic and pro-tumorigenic roles as potential targets for the therapeutic treatment of gonadotroph tumors. Overall design: 6 surgically resected gonadotroph adenomas were dissociated and analyzed using scRNAseq with 10X Genomics. Generation of the library was done using a Chromium controller and v3 reagent kit (10xGenomics). 2 Cryospeserved gonadodotoph adenomas embeded in tissue-TEK were sectioned and sequenced using a Visium Kit (10xGenomics)