Ludwig Cancer Research DPhil Studentships - "Hypoxia signaling in proliferation (and cancer): a balance between HIF-2 and HIF-1"

Hypoxia is common to many cancers, as the oxygen needs of proliferating tumour cells cannot be met via delivery from local blood vessels. Tumour cells must adapt to this reduced oxygen environment in order to survive. This may be achieved through activation of hypoxia-inducible factor (HIF): an alpha/beta heterodimeric transcription factor that directs multiple cellular and systemic responses to changes in oxygen. In the presence of oxygen, HIF prolyl and asparaginyl hydroxylases (PHD1, 2, 3 and FIH, respectively) catalyse post-translational hydroxylation of specific prolyl and asparaginyl residues in HIFalpha subunits (of which there are three: 1, 2 and 3) to promote its degradation via the von Hippel-Lindau E3 ubiquitin ligase (pVHL). In hypoxia, these processes are suppressed and HIF initiates a massive transcriptional cascade to induce processes such as glyolysis and angiogenesis that aid oxygen homeostasis1. In addition, HIF may alter processes such as proliferation and apoptosis that are less obviously concerned with oxygen balance but which may impact tumour growth/survival.

In the case of proliferation, it has long been appreciated that hypoxia induces extensive proliferation in a discrete set of cell types. Of these, one of the best characterized examples is that of the carotid body type I cells of the peripheral nervous system, which sense and respond to low arterial oxygen tensions by enhancing ventilation. These cells undergo dramatic expansion under hypoxia2 to help induce ventilation acclimatization and redress oxygen balance through increased oxygen uptake. The mechanisms involved, however, remain unclear. Disturbances to the HIF signaling pathway via, for example, partial PHD2 inactivation, suggest a role for the HIF system in hypoxia-induced proliferation of carotid body type I cells3. Indeed, emerging data in our laboratory suggests that the balance between HIF-2 and HIF-1 is critical to this process and that these principles apply more generally to other cell types.

This studentship will follow on from these findings by investigating the role of HIF-2 versus HIF-1 in hypoxia-induced proliferation. In the first instance, the extent of hypoxia-induced proliferation will be defined by examining different cell types (for example, other neural tissue). Once identified, the role of HIF-1 versus HIF-2 will be investigated using transgenic mouse models for acute loss of HIF-1 and 2 which are maintained in the laboratory. Downstream pathways (that may involve Cyclin D14 or Oct-45) will be investigated. These findings may then be translated into the clinical setting by examining how the role of HIF-1 and 2 in proliferation (and apoptosis) affects tumour development and whether HIF hydroxylase inhibitors help or exacerbate these actions.

The research project will involve a range of techniques covering both molecular/cellular biology and animal physiology, including:

+ Transgenic models
+ Immunohistochemistry and confocal imaging
+ Western blotting, qPCR
+ In vivo tumour models
+ Monitoring of tumour growth and behaviour by (functional) imaging
+ Analysis of drug action in vivo

We are looking for an exceptional and motivated student with a desire to understand hypoxia physiology/pathology and a willingness to compete at the highest international level. The successful candidate will have a strong track record in a relevant subject and is expected to have good communication skills, attention to detail and an ability to work both independently and as part of a team. Interest and experience in animal physiology would be considered advantageous.

Ludwig Cancer Research is an international non-profit research organisation committed dedicated to preventing and controlling cancer. The Ludwig Cancer Research Oxford Branch, is based within the Nuffield Department of Clinical Medicine at the University of Oxford The overall aim of the Oxford branch is to translate basic discoveries into the clinic for the benefit of patients, with their research helping to aid in the future diagnosis of cancer and the design of more effective, individualised treatments.