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Understanding how to manipulate a tumour's microenvironment and how can use this understanding for therapeutic gain.

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Tumours are not composed of just cancer cells. Instead, in addition to cancer cells a variety of resident and infiltrating host immune cells, secreted factors, extracellular matrix proteins, stromal and epithelial cells are present in tumours. Importantly, tumours (and all the cells in them) also experience environmental factors including low oxygen (hypoxia), acidosis and increased pressure. The term tumour microenvironment (TME) is used to refer to the cellular composition of a tumour and the tumour specific physical factors present. Several aspects of the TME have been shown to drive tumour progression and therapy response. For example, regions of hypoxia lead to therapy resistance (chemo/immuno/radiotherapy) and increased metastasis. Therefore, to understand how tumours develop, improve therapy response, and identify new therapeutic strategies it is imperative that we consider the TME, and not isolated tumour cells grown in standard conditions.

The effect of hypoxia on tumour biology in this context has long been a focus of the Department. Understanding its impact on metastasis, metabolism, DNA damage processing and immune function, and how all these factors affect response to radiation, in particular, are key elements of several programmes. The area is also a pillar of our involvement in RADNET (CRUK’s radiation network). In the Department we have the tools and model systems to map and to manipulate the tumour microenvironment, to better understand and overcome the mechanisms that govern resistance to therapy. We are interested in uncovering the dynamic crosstalk that exists between different components of the TME and how these interactions adapt in response to the selective pressures of stress or treatment. Our ability to integrate physical and traditional oncological sciences has the potential to deliver an internationally leading strength. Our in depth understanding of the consequences of hypoxia and established links with Chemistry, Mathematics and Radiology (amongst others) will allow tumour-specific effects of processes elucidated in other themes to be characterised and modelled, with a growing emphasis on spatial relationships.



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