Endocrine Abstracts (2011) 27 OC1.2

Isolation and characterisation of tumorigenic progenitors/stem cells with a stabilizing mutation in [beta]-catenin, in a mouse model of human adamantinomatous craniopharyngioma

Cynthia L Andoniadou1, Carles Gaston-Masuet1, Paul LeTissier2, Mehul T Dattani1 & Juan Pedro Martinez-Barbera1

1UCL Institute of Child Health, London, UK; 2MRC National Institute for Medical Research, 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 but little is known about their role in tumorigenesis. Adamantinomatous craniopharyngioma (ACP) is the most common paediatric non-neuroepithelial intracerebral tumour, of hitherto unknown cellular origin. ACP has a highly infiltrative nature, often leading to unacceptably high morbidity and mortality following surgical resection as well as high tendency to recur. We recently generated the first genetic mouse model for ACP by conditional expression of a stable form of β-catenin in the pituitary gland, leading to an activation of the Wnt pathway (Hesx1Cre/+;Ctnnb1lox(ex3)/+). Unexpectedly, Wnt signalling activation occurs only in a subset of cells. 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, both of which may contribute to formation of the tumour in the ACP model. Moreover, through isolation of these putative β-catenin accumulating CSCs by flow-sorting, we show that they have functional properties of PSCs. Microarray analysis of these cells has revealed a unique genetic signature, with significant elevation of pathways involved in cancer. We present novel data demonstrating that in human ACP, these pathways are also affected and identify these as important targets for future treatments.