OR24-4 Homeostatic and Tumourigenic Activity of SOX2+ Pituitary Stem Cells is Controlled by the LATS/YAP/TAZ Cascade

Abstract

SOX2 positive pituitary stem cells (PSCs) are specified during embryonic development and persist throughout life, giving rise to all anterior pituitary endocrine lineages. We have previously revealed the activation of the LATS/YAP/TAZ signaling cascade in the developing and postnatal mammalian pituitary1, 2. Here, we demonstrate that this pathway functions during pituitary development and in the regulation of the SOX2 cell compartment. Through loss- and gain-of-function genetic approaches, we reveal that restricting YAP/TAZ activation during development is essential for normal organ size and specification from SOX2+ PSCs. Postnatal deletion of LATS kinases and subsequent upregulation of YAP/TAZ leads to the expansion of the SOX2+ PSCs and disruption of their differentiation, causing the formation of non-secreting, aggressive pituitary tumours. In contrast, sustained expression of YAP alone results in expansion of SOX2+ PSCs capable of differentiation and devoid of tumourigenic potential. Our findings identify the LATS/YAP/TAZ signaling cascade as an integral component of PSC regulation in normal pituitary physiology and tumourigenesis, of relevance to therapeutic and regenerative medicine approaches. 1. Lodge EJ, et al. Expression Analysis of the Hippo Cascade Indicates a Role in Pituitary Stem Cell Development. Front Physiol. 7, 114 (2016). 2. Xekouki P et al. Non-secreting pituitary tumours characterised by enhanced expression of YAP/TAZ. Endocr Relat Cancer. (2018).