Adamantinomatous craniopharyngiomas (ACPs) are clinically challenging tumours, the majority of which have activating mutations in CTNNB1. They are histologically complex, showing solid tumor component comprised of different morphological cell types (e.g. β-catenin accumulating cluster cells and palisading epithelium), surrounded by a florid glial reaction with immune cells, but also a cystic component. ACP cysts often exert substantial mass effect on critical structures, including the pituitary, the hypothalamus, visual pathways and the third ventricle, leading to severe endocrinal and neurological morbidity. This observation allowed to consider cyst-directed therapies that may offer the opportunity to control the local effect of ACP. We have carried out RNA sequencing on 18 ACP samples and integrated these data with an existing ACP transcriptomic datasets. No studies so far have examined the patterns of gene expression within the different cellular compartments of the tumour. We reveal that cell clusters express high levels of several members of the FGF, TGF-β and BMP families of secreted factors, which signal to neighbouring cells as evidenced by immunostaining against the phosphorylated proteins pERK1/2, pSMAD3 and pSMAD1/5/9 in both human and mouse ACP. We determine that inhibiting the MAPK/ERK pathway results in the reduction of tumour cell proliferation and the increase of apoptosis in explant cultures of human and mouse ACP. Current experiments on genetically engineered ACP mouse model are ongoing to assess the effect of Trametinib, a MEK1/2 inhibitor, on the ACP development and to determine the potential therapeutic interest as targeted therapy in the particular environment of cysts development. Our data support a new therapeutic opportunities for ACP patients by revealing the activation of the MAPK/ERK pathway in human ACP and showing that the inhibition of this pathway can affect tumour development.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology