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ERK5 drives immune suppression in cancer


Project Description

The inflammatory microenvironment is arguably one of the most influential components of most, if not all, tumours (1). Central to cancer-related inflammation is a population of macrophages, namely tumour-associated macrophages (TAMs), which primarily originate from blood monocytes that are continuously recruited to the tumour site (2). In early tumours, TAMs display an inflammatory and tumouricidal “M1-like” phenotype. However, as tumours progress, TAMs are functionally reprogrammed by tumour-derived signals to exhibit an immune-inhibitory “M2-like” phenotype, that contributes to further tumour growth and malignancy. Accordingly, the detection of large numbers of TAMs in cancer correlates with poor prognosis, but also with a poor response of the tumour to anticancer agents (3). Based on these observations, a variety of macrophage-targeted interventions have been tested in pre-clinical models with encouraging results (4).

Recently, we have discovered that ablation of the extracellular-regulated protein kinase 5 (ERK5) in macrophages markedly attenuated the growth of carcinoma grafts in vivo. These findings are relevant because aberrant signalling via increased ERK5 expression or activation in human tumours correlates with poor patient outcome (5). Therefore, we anticipate that ERK5 constitutes a potential novel target for anti-TAM therapies.

This project proposes to test this hypothesis and provides strong pre-clinical data for the pathogenic role of ERK5 in TAMs. This will be achieved using relevant models of human cancer exhibiting selective macrophage inactivation of erk5. Using these models, we will employ innovative macrophage-specific in vivo imaging, which enables us to longitudinally quantify both macrophage numbers and their polarisation. In parallel, we will use in vitro cell culture systems to demonstrate direct molecular interactions between tumour cells and macrophages via ERK5.

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent). Candidates with an interest in cancer immunology are encouraged to apply.

Funding Notes

This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

Informal enquiries may be made directly to the primary supervisor.

References

1. Balkwill FR and Mantovani A. Semin Cancer Biol 2012;22:33.
2. Ostuni R et al. Trends Immunol 2015;36:229.
3. Ruffell B and Coussens LM, Cancer Cell 2015;27:462.
4. Mantovani A and Allavena P. J Exp Med 2015;212:435.
5. Simões AE et al. Drug Discov Today 2016.

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