Activating mutations in the gene encoding β-catenin have been identified in the paediatric form of human craniopharyngioma (adamantinomatous craniopharyngioma, ACP), an aggressive pituitary tumour accounting for up to 10% of paediatric intracranial tumours. Recently, we generated an ACP mouse model and revealed that, as in human ACP, nucleocytoplasmic accumulation of β-catenin (βcat-nc) and over-activation of the Wnt/β-catenin pathway occurs only in very few cells that form clusters. Here, combining mouse genetics, fluorescence labeling and flow-sorting techniques, we have isolated these cells from tumorigenic mouse pituitaries and show that the βcat-nc cells contain higher numbers of colony-forming cells when cultured in stem cell-promoting media and have longer telomeres, indicating shared properties with normal pituitary progenitors/stem cells. Global gene profiling analysis has revealed that these βcat-nc cells express high levels of secreted mitogenic signals and several chemokines and their receptors, suggesting an important non-cell autonomous role of these cells in the pathogenesis of ACP and a reciprocal communication with their environment. Finally, endorsing these findings with clinical relevance, we show that these pathways are also elevated in the βcat-nc cell clusters identified in human ACP. Alongside providing further support to the concept that pituitary stem cells may play an important role in the aetiology and/or pathogenesis of human ACP, our data reveal novel potential pharmacological targets for the treatment of these devastating childhood tumours.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: Declaration of Funding: This research was supported by The Wellcome Trust (grant numbers 084361, 078432, and 086545).