Defining pro-tumourigenic neutrophil phenotypes and tumour-neutrophil interactions to identify targets for therapy in metastatic colorectal cancer

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Patients that die from colorectal cancer do so as a result of metastatic disease. The most common site for colorectal metastases is the liver. If liver metastases can be detected early then patients receive the best outcomes following surgery. Sadly there are groups of patients that do very poorly following liver resection. This research looks to identify the patients that do poorly following surgery, understand their disease biology better and provide them with the hope of individually targeted therapy for their cancer in the future.To develop new therapies I have performed assessment of patients with colorectal cancer that have early recurrence and poor cancer related survival following resection of their colorectal liver metastases. It is accepted that patients with high levels of supportive connective tissue surrounding cancer cells, within their metastases have poorer outcomes and this is further supported by analysis in our cohort of patients. My work has shown that these patients have very high numbers of neutrophils, the most common white blood cell, within their metastases. Using mouse models that mimic human pancreatic and colorectal cancer I have shown that in these metastatic cancers neutrophils play an important role in supporting progression of disease, suggesting this phenomenon may not be unique to advanced colorectal cancer. Strikingly, interfering with neutrophils travelling to the liver reduces the number of tumours in the liver and when therapies that activate the immune system are given I can improve survival of the cancer mouse models. Only recently studies have suggested that neutrophils can behave in different fashions, adopting different roles in health and disease. These cells are very plastic and readily change what they express in response to signals from cancer cells and therefore can demonstrate both pro and anti-cancer properties depending on context. It is this plasticity of neutrophils that may lend itself to therapies that modulate the behaviour of the immune system.The questions that remain are: how do neutrophils support progression of metastatic cancer?; What markers do neutrophils that exist in colorectal cancer metastases express and how do these support their function in cancer progression compared with in health? One important consideration is that neutrophils are important for normal immunity to fight off disease and by specifically targeting tumour promoting neutrophils future therapies may negotiate difficulties with innate immunity.In this proposal I will address in detail which patients have high numbers of neutrophils associated with metastases by subtyping patients according to their disease biology using sequencing of molecular factors produced by the tumours. Using exciting new technologies that have been developed by an industry partner, Nanostring, I will then resolve the question of which types of neutrophils are present by performing in-depth spatially orientated assessment of neutrophil populations in liver tumours. Once I have identified neutrophil populations associated with aggressive disease biology I will use a state of the art mouse model of colorectal cancer metastasis I have developed in the laboratory to remove different populations of neutrophils within a living system most relevant to the human disease and assess the impact on the metastatic process using sophisticated microscopy of the mouse as metastases develop. These assessments will demonstrate the impact of these targeted approaches on the behaviour of neutrophils, interactions with immune and tumour cells and ultimately on mechanisms by which colorectal cancer spreads. Using the mouse model in a high throughput manner, where I test a number of molecular factors knocked out on neutrophils within the metastatic tumour system, I will be able to identify potential targets on neutrophils that could be used for therapy in future clinical trial.