Endocrine Abstracts

Background: Senescence is a cellular process that is normally associated with ageing. In fact, senescent cells are rare in the tissues of children and young adults. However, our research has shown that adamantinomatous craniopharyngioma (ACP), a clinically aggressive paediatric pituitary tumour, contain cells that express the hallmarks of cellular senescence and senescence associated secretory phenotype (SASP). Moreover, we have hypothesised that these senescent cells, through their SASP, promote tumourigenesis in both mouse and human ACP. To test this hypothesis, we have analysed the effects of the ablation of senescent cells and modulation of their SASP using genetic ACP mouse models and pharmacological approaches.

Methods: Genetic murine ACP models that mimic human ACP (Hesx1^Cre/+; Ctnnb1^loxex3/+ and the inducible adult Sox2^CreERT2/+; Ctnnb1^loxex3/+ models) were used. ACP models were combined with a novel p21-stop-FDR mouse model, which expresses a fusion protein of diphtheria toxin receptor (DTR) with a fluorescent mCherry reporter from the Cdkn1a (p21) locus. This mouse model can report and ablate p21-expressing cells, including the senescent cluster cells in the ACP models. The ACP models were also combined with a new R26-stop-mBRF1 model, which allows attenuation of the SASP by degrading the mRNAs of many inflammatory SASP factors. In-vivo survival studies, ex vivo culture and immunohistochemical characterizations were carried out.

Results: Ablation of senescent cluster cells or attenuation of the SASP using genetic mouse models, leads to asignificant reduction in ACP tumour burden and increased mouse survival. In addition to inhibitors of anti-apoptotic proteins, we show that a new senolytic compound targeting the ER-Golgi protein transport machinery can also ablate senescent cluster cells in ACP mouse models ex-vivo.

Conclusion: Our results demonstrate a critical role of senescent cells in ACP tumourigenesis and identify these cells as potential targets for senotherapies.