Children’s Cancer and Leukaemia Group (CCLG) McElwain Award winner – Adamantinomatous craniopharyngioma contains senescent cells with tumour-inducing potential

Mario Jose Gonzalez-Meljem1,Gabriela Carreno1,John Apps1,Scott Haston1,Christina Stache1,Tomas Stanley Jacques2,5,Colin Goding3,Jesus Gil4,Cynthia Lilian Andoniadou1,Juan Pedro Martinez-Barbera1

1University College London, London, UK,2University of Oxford, Oxford, UK,3Imperial College London, London, UK,4King’s College London, London, UK,5Great Ormond Street Hospital, London, UK

Presenting date: Wednesday 4 November
Presenting time: 10.30 - 10.45

Background

Adamantinomatous craniopharyngioma (ACP) is a paediatric pituitary tumour that is associated with high morbidity due to the tendency of the tumour to infiltrate locally into surrounding brain structures such as the hypothalamus and visual tracts. We have developed and validated two mouse models for human ACP, which have provided original insights into the aetiology and pathogenesis of human ACP (1-3). Recently, we revealed a novel and intriguing mechanism by which Sox2+ve pituitary stem cells contribute to oncogenesis, which is fundamentally different to the classical cancer stem cell paradigm. When targeted to express oncogenic beta-catenin, mutant Sox2+ve stem cells do not give rise to the progeny populating the tumour, instead these oncogenic stem cells induce tumorigenesis in a paracrine manner (3). Our current research aims to dissect the molecular and cellular mechanisms underlying this paracrine involvement for stem cells in tumorigenesis.

Method

We use a multidisciplinary approach combining state-of-the-art mouse genetics with histological, molecular and stem cell biology methods. We use our ACP mouse models to investigate basic mechanisms, which are subsequently validated in human samples of ACP available to us through the GOSH hospital.

Results

Our research indicates that senescence and the senescence-associated secretory phenotype are critical players for tumour initiation. Specifically, we show that following a short burst of proliferation, oncogenic Sox2+ve cells stop dividing to form beta-catenin-accumulating cell clusters that become senescent. These clusters show senescence-associated beta-galactosidase activity, p53 pathway activation and up-regulate the expression of the cell cycle inhibitors p21 and p16. Additionally, cluster cells show elevated expression of lysosomal components and activate the autophagy pathway. Oncogenic beta-catenin also causes DNA damage as evidenced by an increase in H2A.X phosphorylation, triggering the DNA damage response. As a consequence, NF-kB signalling is elevated resulting in the expression of activation a Senescence-Associated Secretory Phenotype (SASP) with expression of multiple secreted factors including pro-inflammatory cytokines such as IL1, IL6 and IL8. Of translational significance, we show that this mechanism is relevant in human ACP tumorigenesis. Beta-catenin-accumulating cell clusters in human ACP express several senescence markers such as p21, p16 and lysosomal enzymes, exhibit DNA damage and activate P53, NF-kB and autophagy pathways, resulting in SASP activation.

Conclusion

Together, the mouse and human data suggest that senescence and SASP are likely to modify the tumour microenvironment resulting in cell transformation and tumour growth.