| dc.description.abstract | Craniopharyngiomas are hypothalamic-pituitary axis tumours which are clinically difficult to manage. There are two histological subtypes. Adamantinomatous craniopharyngiomas (ACPs) tend to present in childhood with 70% of cases associated with activating mutations in the CTNNB1 gene within pituitary stem cells (PSCs). Papillary craniopharyngiomas (PCPs) present in adults and are associated with activating BRafV600E mutations. Treatment with total surgical resection is often unobtainable without causing significant co-morbidity, leading to high recurrence rates. Previous studies have highlighted the presence of inflammation within established human and mouse ACPs, yet little is understood about the early tumour microenvironment (TME) of ACPs and the role of immune cells in early ACP formation. Through generation of two murine models of ACP, the very early immune infiltrate within the TME of ACPs was evaluated and characterised. This identified an immune infiltrate of predominantly myeloid lineage detectable within five days of oncogenic β-catenin activation. Use of a fluorescent Wnt/β-catenin responsive reporter within one model enabled isolation of tumour initiating Sox2 positive PSCs from PSCs refractory to oncogenic β-catenin activation. Subsequent subpopulation transcriptomic analysis identified several upregulated genes mapping to inflammatory pathways, and several cytokines/chemokines important for the recruitment and maturation of macrophages, neutrophils, dendritic cells, T cells and NK cells. Furthermore, tumour initiating PSCs were identified as a source of pro-inflammatory cytokines/chemokines mapping to the IL-6-JAK-STAT pathway. While treatment with anti-IL-6 monoclonal antibody in vitro failed to show any effect on tumour cell growth, treatment with a novel BRaf inhibitor showed significant reduction in colony formation of ACP derived PSC culture, confirming an important role of the MAPK pathway in ACPs. Identification of this key immune signature during early ACP formation has highlighted possible therapeutic targets such as chemokine receptors crucial for the recruitment of macrophages and paves the way for cellular targeting of the TME in ACPs. | en_US |
