Endocrine Abstracts

The Hippo kinase cascade is a crucial signalling pathway regulating organ growth during development in numerous organs. There is mounting evidence implicating this signalling pathway in tumour formation, where it is emerging as an anti-cancer target due to effective pharmacological inhibition of its transcriptional activators YAP/TAZ. We previously demonstrated activity of the Hippo kinase cascade in the mouse pituitary and nuclear association of YAP/TAZ with SOX2 expressing pituitary stem cells. Here we sought to investigate whether these components are expressed in the human pituitary and if their expression may be deranged in human pituitary tumours. We analysed pathway component expression by immunofluorescence during human pituitary gland development, in the adult pituitary, null cell non-functioning pituitary adenomas (NFPAs), adamantinomatous craniopharyngiomas (ACPs), papillary craniopharyngiomas (PCPs) and prolactinomas. We find that the Hippo pathway is active during human pituitary development and adulthood and that YAP/TAZ are expressed in a similar pattern to SOX2 positive cells. Our data reveal an enrichment of YAP/TAZ in the majority of non-sereting tumours, in contrast to differentiated tumours, which display low or absent levels. To determine the effect of this pathway on endocrine cell type differentiation, we knocked down Lats1, encoding the kinase responsible for phosphorylating and inactivating YAP/TAZ, in the GH3 rat mammosomatotropinoma cells. Loss of LATS1 led to accumulation of both proteins and suppressed Prl and Gh promoter activity. In conclusion, we have demonstrated activity of the Hippo kinase cascade in the human pituitary and association of YAP/TAZ with the undifferentiated state both in vitro in GH3 cells and in vivo in the normal pituitary and pituitary tumours. Characterisation of this pathway in pituitary tumours is of potential prognostic value, opening up putative avenues for treatments combating tissue growth.