Phaeochromocytomas are catecholamine producing neuroendocrine tumours that derive from chromaffin tissue of the adrenal medulla and extra-adrenal paraganglia. A substantial proportion of the tumours have a hereditary basis. These display distinct differences in gene expression profiles with resulting highly heterogeneous clinical presentations depending on the mutation. The tumours produce variable amounts of the three catecholamines, adrenaline, dopamine and noradrenaline, have different adrenal and extra-adrenal locations and related variable propensities to malignancy. This project will investigate the basis for reciprocal up-regulation of hypoxia-response pathways and down-regulation of Krebs cycle energy pathways in chromaffin cell tumours characterised by immature catecholamine biosynthetic and secretory phenotypes and aggressive behaviour. Data from clinical investigations in patients with different forms of the tumour combined with studies utilising tumour samples (including primary cultures) will be used in conjunction with model systems to establish mechanistic links between hypoxia response pathways and catecholamine and energy pathway metabolomes. The project will thereby facilitate improved understanding of tumourigenic processes, development of tumour biomarkers and identification of targets for therapy; this is not only relevant to patients with chromaffin cell tumours, but also has implications for more common neoplasms.