Endocrine Abstracts

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 longer telomeres, indicating shared properties with normal pituitary progenitors/stem cells (PSCs). Global gene profiling analysis has revealed that these βcat-nc cells express high levels of factors encoding secreted mitogenic signals, such as members of the SHH, BMP and FGF family, in addition to 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. Through genetic approaches utilising inducible Cre mouse lines, we are targeting PSCs to exclusively sustain the activating mutation in β-catenin and assess if this leads to a pre-tumoral lesion. Alongside providing further support to the concept that PSCs may play an important role in the aetiology and/or pathogenesis of human ACP, our data reveal novel disease biomarkers and potential pharmacological targets for the treatment of these devastating childhood tumours.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details unavailable.