Authors
James Blackburn, James G Nicholson, Laura Gomez-Corral, Jingyi Xue, Ashutosh Rai, Bryan Padraig Finn, Rachael J L Tan, Kalyana C Chakravarthi, Angelica Gualtieri, Charlotte L Hall, Gabor Czibik, Pinaki Dutta, Márta Korbonits, Federico Roncaroli, Shannon W Davis, Carles Gaston-Massuet
Published in
EMBO molecular medicine. Oct 09, 2026. Epub Oct 09, 2026.
Abstract
Adamantinomatous craniopharyngiomas (aCPs) are complex intracranial neoplasms that arise in the sellar and suprasellar region of the brain, affecting the endocrine and nervous systems, causing severe sequelae. Although most of aCPs are driven by somatic mutations in β-catenin (CTNNB1), some cases remain genetically unresolved. Here, we show that disruption of the Wnt-antagonist and tumour suppressor adenomatous polyposis coli (Apc) leads to pituitary tumours that present all classic molecular and histopathological hallmarks of aCPs. Mechanistically, we show that a hypomorphic allele of Apc leads to tumour development and that bi-allelic loss of Apc in the Sox2+ve pituitary stem cells can initiate aCP formation. Apc-driven tumour-initiating cells show a distinct transcriptional signature of p21-mediated senescence-associated secretory phenotype (SASP) with methylomic analyses revealing shared epigenetic alteration of SASP-like inflammatory programme across aCP subtypes. Our data demonstrate a causal role of disruption of Apc in driving aCPs, reinforcing the importance of genetic testing for mutations in APC in patients with aCP. Furthermore, our work highlights the need to screen patients with familial adenomatous polyposis (FAP) or the spectrum of APC-pathogenic syndromes for aCP development early in life.
PMID:
42855520
Bibliographic data and abstract were imported from PubMed on 10 Oct 2026.
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