Endocrine Abstracts

Background: Adamantinomatous craniopharyngiomas (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 from of ß-catenin are the main driver for many of these neoplasms. However, underlying genetic drivers for a number of tumours remains unknown.

Aims: To determine if disruption the Wnt inhibitor, adenomatous polyposis coli (APC), can lead to aCP tumorigenesis independent of ß-catenin mutations.

Methods: To demonstrate that APC can be a driver of aCPs independent of β-catenin, two novel transgenic murine lines were created. Using the pituitary specific Cre driver, Prop1:Cre, the large final coding exon of Apc was deleted, in the other model a hypomorph allele was created. Detailed phenotypic assessment was performed using immunofluorescence, in-situ hybridisation and mRNA sequencing of tumour initiating cells.

Results: Phenotyping of both models shows that Apc can drive aCP tumour formation. These tumours present with all histological and molecular hallmarks of aCPs. The hypomorphic allele for Apc leads to postnatal tumour development, indicating that disruption of Apc function alone, is sufficient to drive aCP formation independent of ß-catenin mutations. This model also developed a phenotype of hypothalamic damage, with morbid obesity developing in early adulthood. Transcriptomic analyses of early tumour-initiating cells reveal early clusters of accumulating ß-catenin undergo senescence, which differs molecularly to ß-catenin positive tumours.

Discussion: Our results show that disruption of Apc leads to the development of aCPs independent of ß-catenin. The two novel genetic models highlight the phenotypic variability aCPs and form a basis for further study of this heterogeneity. The onset of tumours in the postnatal period and the development of hypothalamic obesity, provides an opportunity to develop therapeutic agents to target tumour development and hypothalamic sequelae of the tumour. Together our findings reinforce the need for genetic testing for mutations in APC in patient with aCP, and the increased surveillance of patients with APC-pathogenic syndromes for the development of aCPs as part of their phenotypic spectrum.