Disruption of the Wnt-antagonist APC in the pituitary stem cells drives adamantinomatous craniopharyngioma
Adamantinomatous craniopharyngioma (aPCs) are complex intracranial neoplasms that arise in the sellar or parasellar region affecting the endocrine system and leading to severe comorbidities. Activating mutations resulting in degradation resistant from of  b-Catenin (CTNNB1 gene) have been shown to be the main driver for a large proportion of these neoplasms. However, the underlying genetic driver for a proportion of these tumours is still unknown. Using murine transgenic models, we show that genetic deletion of the Wnt-antagonist and tumour suppressor, Adenomatous Polyposis Coli (Apc) within the pituitary progenitors/stem cells leads to pituitary tumours that closely resemble human aCPs. These tumours present classical histopathological hallmarks of aCPs such as clusters of accumulating nuclear b-catenin that are slow dividing and undergo secretory phenotype. These tumours present wet keratin, stellar-reticular-like structures and cystic components. We show that a hypomorphic allele of Apc is sufficient for tumour development indicating that disruption of Apc function can lead to aCP formation independent of b-Catenin mutations. Moreover, we identify that bi-allelic loss of Apc in the Sox2+ve pituitary stem cells is sufficient to initiate tumour formation, indicating that Sox2+ve stem cells are the cell origin of these Apc-driven tumours. Transcriptomic analyses of early tumour-initiating cells reveal that clusters of accumulating b-Catenin, undergo p21-mediated cellular senescence and that the secretory phenotype is composed of inflammasome, angiosome and developmental growth factors which are different from the   b-Catenin-driven aCP tumours. Our data, unequivocally shows, that disruption of the tumour suppressor Apc in the pituitary progenitors/stem cells is a main driver of aCPs independent of mutations in b-Catenin. We provide two novel murine models that represents a genetic subtype of aCPs which helps to further understand aCP pathogenesis. Overall design: Transcriptomic analyses comparing FAC-sorted purified APC-mutant cells compared to wildtype pituitary stem cells to identify the gene regulatory network downstream of oncogenic APC in pituitary tumours