Investigating the role of electrophysiological chemosensitivity in oncogenesis

Hypoxia-inducible factor (HIF), a transcription factor that mounts gene expression changes to low oxygen, is commonly activated in cancer and its role in oncogenesis has attracted widespread interest. Although HIF operates ubiquitously across cell types and is commonly upregulated in cancer, direct genetic activation by mutation of any of the key components of the HIF pathway is rare in most forms of cancer. An important exception to this are tumours of the autonomic paraganglia, known as pheochromocytomas and paragangliomas (PPGLs). These tumours are highly heritable with almost half of these tumours bearing an inherited, germline mutation and mutations that result in activation of HIF (in the absence of hypoxia per se i.e. ‘pseudohypoxia’) are particularly common. We have recently demonstrated that persistent activation of HIF-2 in sympathoadrenal cells results in the development of an abdominal paraganglioma through retention and expansion of the foetal organ of Zuckerkandl(1), accompanied by the presence of ectopic chromaffin cells distributed between it and the adrenal gland(2). Importantly, overactivity of HIF-2 within these cells produced a gene expression pattern more consistent with that observed in specialised oxygen sensing cells of the carotid body(1). Indeed, these retained paraganglia also displayed remarkable oxygen chemosensitivity(1), a property only described in such cells during the neonatal period. This characteristic is exemplified by rapid electrophysiological excitability in response to physiological changes in oxygen availability, and is associated with the secretion of catecholamine neurotransmitters to coordinate cardiorespiratory reflexes aim at oxygen normalisation. Notably, carotid body hyperplasia has been observed following exposure to chronic hypoxia(3), a phenomenon thought to be due to persistent stimulation(4). This relationship between electrophysiological activity and aberrant proliferation has also been observed in glioblastoma(5, 6) and small cell lung cancer(7). This project aims to test the connection between oxygen chemosensitivity and the growth of paragangliomas, with a view towards developing new translational opportunities to treat such tumours.

Training

The student will be trained in a range of molecular biological techniques such as; cell culture, immunoblotting, RT-qPCR, and cloning, as well as real-time measurements of electrophysiological function using live cell fluorescence measurements with genetically encoded sensor proteins. A major aim of the project will be to generate and characterise a cell line that demonstrates oxygen chemosensitivity, either through explanation from appropriate mouse tissues or via transgenic expression of relevant proteins in existing cell lines.

Funding Notes

Ludwig studentships provide 4 years funding for a tax-free stipend, currently £21,000 pa and university fees at home and international rates.

Only applications made by the University of Oxford application system for a DPhil in Clinical Medicine will be considered. You may apply for a maximum of two Ludwig projects. Under proposed field and title of research project please enter the project titles in the order of preference. You do not need to provide a research proposal but must include a personal statement.

Please ensure referees are willing to write and submit your reference by the deadline.

Enquiries

Alexandra Royer – alexandra.ward@ludwig.ox.ac.uk – application related enquiries

Applications

https://www.ox.ac.uk/admissions/graduate/courses/dphil-clinical-medicine