ESPE Abstracts

Introduction: Adamantinomatous craniopharyngioma (aPCs) are complex intracranial neoplasms that arise in the sellar or parasellar region affecting the endocrine system, leading to severe comorbidities. Activating mutations resulting in degradation resistant b-Catenin have been shown to be the main driver for a large proportion of these neoplasms. However, the underlying genetic driver for a number of these tumours remains unknown. Here, using murine transgenics, we demonstrate that disruption of the tumour suppressor Apc leads to aCP tumours independent of b-Catenin mutations.

Methods: We have generated two novel transgenic murine models: one where the final large coding exon of Apc has been genetically deleted using a pituitary specific Cre driver (Prop1Cre) and a second model of hypomorph allele for Apc. Deep phenotyping of both lines was performed using immunofluorescence, in situ hybridisation combined with mRNA-sequencing of tumour initiating cells.

Results: We show that genetic deletion of the Wnt-antagonist and tumour suppressor, Adenomatous polyposis coli (Apc), in pituitary cells, leads to pituitary tumours that closely resemble human aCPs. These tumours present all the classical histopathological hallmarks of aCPs including clusters of accumulating nuclear b-catenin, wet keratin, stellate reticulum-like cells, and cystic components. We show that a hypomorphic allele for Apc leads to tumour development indicating that disruption of Apc function alone, is sufficient to 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 can initiate aCP-tumour formation, indicating that Sox2+ve stem cells are the cell origin of these Apc -driven tumours. Transcriptomic analyses of early tumour initiating cells reveals that early clusters which accumulate b-Catenin, undergo cellular senescence which differ molecularly to their b-catenin+ve tumour counterparts. These early lesions undergo senesce-mediated secretory phenotype composed primarily of pro-inflammatory and pro-angiogenic factors. Moreover, postnatal phenotyping reveals hypothalamic involvement due to tumour hypothalamic damage leading to aCP-mediated obesity.

Conclusion: Our data shows that disruption of the tumour suppressor Apc in pituitary progenitors/stem cells is a key driver for aCPs that acts independent of mutations in b-Catenin. We provide two novel murine models that explain the genetic heterogenicity of aCPs and represent a genetic subtype of aCP-tumours, helping to further understand the pathogenesis of aCPs. Together our findings reinforce the need for genetic testing of patients with aCPs, and suggest APC should be considered as part of this. We also suggest that patients with germline APC mutations may be at higher risk of aCP development.