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Title: The molecular pathogenesis and diagnosis of phaeochromocytoma : roles for primary cilia and adrenal venous sampling?
Author: O'Toole, Samuel Matthew
ISNI:       0000 0004 8503 9958
Awarding Body: Queen Mary University of London
Current Institution: Queen Mary, University of London
Date of Award: 2019
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Primary cilia are microtubule-based cellular organelles that project into the extracellular space. They subserve a wide range of sensory stimuli, co-ordinate and modulate a number of signalling pathways and are intrinsically linked to the cell cycle and its progression. Cilia loss is frequently observed in tumours; yet, the responsible mechanisms and consequences for tumourigenesis remain unclear. The aim of this thesis is to examine the role of primary cilia in the pathogenesis of phaeochromocytomas (life-threatening catecholamine-producing neuroendocrine tumours of the adrenal medulla). We demonstrate that primary cilia are lost in phaeochromocytomas compared to adjacent noncancerous tissue. These structural changes are associated with transcriptional alterations within cilia-mediated signaling pathways that are associated with tumorigenesis generally and phaeochromocytomas specifically. Importantly, cilia loss is most dramatic in patients with germline mutations in the pseudohypoxia-linked genes SDHx and VHL. Using a phaeochromocytoma-derived cell line, we show that hypoxia and oncometabolite-induced pseudohypoxia are key drivers of cilia loss and identify that this is dependent on activation of the Aurora-A/HDAC6 cilia resorption pathway. We also show that cilia loss drives transcriptional changes associated with proliferation and tumourigenesis. Our data provide evidence for primary cilia dysfunction contributing to phaeochromocytoma pathogenesis through a hypoxic/pseudohypoxic mechanism and implicate oncometabolites as ciliary regulators. These findings have relevance beyond phaeochromocytomas as hypoxia is a general feature of the tumour microenvironment and the resultant ciliary resorption can be pharmacologically inhibited, suggesting a potential therapeutic target. Further studies demonstrate that additional features of the phaeochromocytoma microenvironment, namely catecholamines, also impact on primary cilia expanding our understanding of the role of this organelle. Finally, we provide normative reference intervals for adrenal venous catecholamines facilitating accurate diagnosis of phaeochromocytomas for use in situations where localisation cannot be reliably achieved by standard imaging approaches alone.
Supervisor: Not available Sponsor: Barts Charity Clinical Research Training Fellowship
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Primary cilia ; tumourigenesis ; phaeochromocytomas ; neuroendocrine tumours