Investigating the role of Aip in pituitary tumourigenesis

Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene predispose to hormone secreting pituitary tumours1. Patients with AIP mutation positive pituitary tumours suffer from significant morbidities, including biventricular hypertrophy and diastolic dysfunction, progressing to fulminant cardiac failure if left untreated2. Current treatments include the lack of an effective drug for the majority of patients resulting in the need for surgical resection and adjuvant radiotherapy that comes with the risk of severe sequelae3. Animal models of acromegaly are scarce, and Aip models have controversial data. The aims of this study include generating, characterising and ultimately, using genetically engineered mouse models of Aip-related acromegaly to investigate the mechanism behind the loss of Aip in pursuit of identifying novel candidate genes and pathways that may serve as therapeutic targets. Our AipFlox/Flox; Hesx1Cre/+ model abrogates Aip in cells expressing the early pituitary transcription factor Hesx1, specifically targeting the anterior pituitary at embryonic stage 8.5dpc. Data on these mice suggest that the excess GH from these tumours recapitulate the phenotype similar to human acromegaly. Including an increase in weight and body size of mutant animals, increased circulating IGF-1 levels, enlargement of the pituitary gland and most importantly formation of functional pituitary tumours. Assessment of their hearts confirm progressive heart disease characterised by concentric biventricular hypertrophy, much like human patients. Exploration of the somatostatin analogue response confirm a pasireotide response on the weight and IGF-1 and a direct effect of octreotide on the hearts of the animals. RNA sequencing analyses revealed a potential relationship between loss of Aip and the focal adhesion pathway which was explored in vitro and in the AipFlox/Flox; Hesx1Cre/+ mice. I also characterised the inducible AipFlox/Flox; Sox2CreERT2/+ model which deleted Aip in the stem-cell niche of the pituitary and the findings support the phenotype of the AipFlox/Flox; Hesx1Cre/+ model. Finally, a non-Aip related model (Rosa26rtTA/rtTA; TetO-GsTg/Tg; Gh-CreTg/+) was introduced to provide an invaluable tool and useful comparator for the AipFlox/Flox; Hesx1Cre/+ model, supporting continued research on Aip-related tumourigenesis