Apc-deficient pituitary stem cells drive adamantinomatous craniopharyngioma through senescence-associated inflammation.

APC

Loss of Apc function (hypomorphic allele or bi-allelic loss) in Sox2+ pituitary stem cells in the mouse, with a p21-mediated senescence-associated secretory phenotype (SASP)

Adamantinomatous craniopharyngiomas (aCPs) are mostly driven by somatic CTNNB1 (β-catenin) mutations, but some cases remain genetically unresolved. In this mouse study, disruption of the Wnt antagonist and tumour suppressor Apc leads to pituitary tumours displaying all classic molecular and histopathological hallmarks of aCPs. A hypomorphic Apc allele leads to tumour development, and bi-allelic loss of Apc in Sox2+ pituitary stem cells can initiate aCP formation. Tumour-initiating cells show a transcriptional signature of p21-mediated senescence-associated secretory phenotype (SASP), and methylomic analyses reveal a shared epigenetic alteration of this inflammatory programme across aCP subtypes.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This is a mouse study: it establishes a causal link between Apc loss and aCP in an animal model, but the abstract reports no patient carrying a germline APC variant with aCP. The authors draw two recommendations (testing aCP patients for APC variants, and screening patients with FAP or APC-related syndromes early in life) that need clinical data before carrier surveillance is changed. The hypothesis is worth keeping in mind for a genetically unresolved craniopharyngioma.

Analysis by Dr Thibaut Benquey