Weibel-Palade bodies and Golgi apparatus

This project is now closed

Hypoxia, redox signalling & cancer metabolism

Project supervisor: Dimitrios Anastasiou (Physiology and Metabolism)

This project will investigate the roles of hypoxia-induced reactive oxygen species (ROS) in regulating cancer cell metabolism.

Hypoxia (limited oxygen availability) is thought to be a key driver in cancer development. Some of the major effects of hypoxia on cellular physiology are implemented by altering gene expression through the hypoxia inducible factor (HIF) family of transcription factors. However, under certain physiological conditions, such as during development, neovascularisation and stem cell homing, fluctuations in oxygen availability may occur more rapidly than the time required for a transcriptional response. How cells adapt and survive acute changes in oxygen tension within their microenvironment remains largely unknown.

Among others, hypoxia leads to increased levels of ROS. We have recently demonstrated that hypoxia-induced ROS lead to alterations in glucose metabolism by inhibiting the activity of the glycolytic enzyme PKM2 through oxidation of one of its cysteines (Anastasiou et al, 2011). This metabolic reprogramming is necessary for cancer cells to survive under oxidative stress, a condition they are particularly prone to encounter during multiple stages of tumorigenesis.

To understand how ROS mediate global metabolic changes under hypoxia, we undertook a chemical biological approach and used mass spectrometry to identify proteins that harbour oxidized functional cysteines following acute exposure to hypoxia. Among the hits of this screen are several proteins involved in mitochondrial metabolism. The goal of this project is to investigate the role of these ROS-mediated signalling events in mitochondrial function by manipulating the activities of the identified enzymes in cells, and by assessing their effects on metabolism using metabolomics.

This interdisciplinary project offers the opportunity to contribute critical new insights into hypoxia signalling, a fundamental aspect of tumour biology, while providing a solid training in a broad range of techniques (biochemistry, cell biology, quantitative proteomics and analysis of metabolic phenotypes using mass spectrometry-based metabolomics).

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