ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2011) 25 P235

Cancer stem cells with a stabilising mutation in beta-catenin are implicated in the aetiology of human adamantinomatous craniopharyngioma

Cynthia Lilian Andoniadou1, Carles Gaston-Massuet1, Paul Le Tissier2, Mehul Dattani1,3 & Juan Pedro Martinez-Barbera1

1UCL Institute of Child Health, London, UK; 2MRC National Institute for Medical Research, London, UK; 3Great Ormond Street Hospital for Children, London, UK.

Somatic stem cells of multiple tissues such as brain, blood, gut epithelium and epidermis, have specific roles in tissue homeostasis and plasticity of cell types. There is evidence that, when mutated, such cells, termed cancer stem cells (CSCs), also underlie tumorigenesis, but their presence in many tumours is elusive. In the pituitary gland, somatic stem cells (PSCs) have been previously identified and characterised in vitro and in vivo, but so far there is no evidence that PSCs may underlie the formation of pituitary tumours. We recently generated a genetic mouse model for adamantinomatous craniopharyngioma (ACP) by conditionally expressing in the pituitary a stable form of beta-catenin that cannot be degraded, leading to an activation of the Wnt pathway (Hesx1Cre/+;Ctnnb1lox(ex3)/+). Unexpectedly, Wnt signalling activation occurs only in a subset of cells, despite all pituitary cells carrying the mutation. Phenotypic analyses reveal that these cells are quiescent in vivo, are undifferentiated and express SOX2 but not SOX9, all of which are features of the PSC population. Combining in vitro stem cell culture and time-lapse microscopy, we demonstrate that there is both an expansion of the PSC population and an increase in their proliferation rate in our mouse ACP model, both of which may contribute to formation of the tumour. Moreover, through flow-sorting isolate of the putative beta-catenin accumulating CSCs, we show that they have functional properties of PSCs and also reveal their unique genetic signature through microarray analysis. Finally, we show that human ACP also displays beta-catenin accumulating clusters in which the cells demonstrate similar characteristics to PSCs, strongly suggesting that ACP shares a CSC origin in both mouse and human.

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