Multi-Modal analysis of composition and spatial architecture in human premalignant pancreatic lesions to enhance early detection.

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Pancreatic cancer remains a disease with a poor overall prognosis. Many patients have advanced cancer by the time they develop symptoms. Only 1 in 20 patients will be alive 5 years after diagnosis. Prompt investigation, diagnosis and treatment are essential for any possibility of a cure, which requires a combination of early surgery and chemotherapy. Often these cancers develop from pancreatic cysts particularly an Intraductal Papillary Mucinous Neoplasms (IPMN). The widespread use of CT and MRI scans has dramatically increased discovery of these pancreatic cysts. Subsequent monitoring these cysts consumes a great amount of NHS resources. However, the risk of a cancer developing within a cyst is often very difficult to determine. Therefore, the optimal management of pancreatic cysts remains a significant clinical dilemma. The stakes are high, as pancreatic cancer has profoundly poor outcome, yet pancreatic surgery to remove the cyst carries with it on average a 5% risk of death. Therefore, a real risk of unnecessary investigation and treatment exists for many patients with pancreatic cysts. To help us better select patients for treatment, there is an urgent need for novel approaches to improve our understanding of pre-cancerous pancreatic cysts at a cellular level. We need to uncover changes in these cysts, before they develop into pancreatic cancer, and determine why the immune systems fails to stop the cancer growing. Previously, to measure which genes were 'switched-on', tumour samples had to be digested and so the 'geography' of where tumour and immune cells were positioned on the 'cancer battlefield' was lost. This project will have a three-pronged approach to overcome this challenge. Firstly, we will study tissue removed at surgery from patients with pancreatic cysts and cancer using new gene-mapping technology. Maintaining this geography will help us to understand the complex relationship between genes that are 'switched-on' in different regions of the cysts as they growth and progress. Next we will study the 'cancer immune battlefield', to help us understand the: Location, Activity, Inter-relationships between the immune cells and pancreatic cancer cells as they evolve from the lining of the pancreatic cysts. Finally, from pancreatic cysts resected from patients, we will grow tumour organoids. These miniaturised versions of a tumour are grown in the laboratory through three dimensional techniques to better mimic the original tumour. Using these mini-versions of the cyst tumours, we will 'switch on and off' important genes using gene editing techniques to identify those features that turn a low-risk cyst into a pancreatic cancer. Drugs treatments will also be trialled to slow the transformation into cancer. The project will be undertaken by a surgical trainee who has taken time out of his clinical training to focus on research. They will be supported by a team of surgeon scientists, and a world leading laboratory of scientists who create models of pancreatic cancer. Further support will be provided by the Wellcome Trust Sanger Institute who will assist in growing organoids and an international group of surgeons and pathologists with expertise in the management of patients with pancreatic cysts from Verona, Italy. This work has potential to impact the management of an almost incurable disease. Firstly, through the discovery of new markers to help with the detection of pancreatic cancer earlier, at a stage when cure is more likely. Secondly by identifying targets for drugs to slow or prevent pancreatic cancer developing in precancerous cysts.Ultimately, we hope this project will individualise treatment for each patient. Helping to improve our ability to detect on a scan or blood test those cysts at high-risk of becoming a pancreatic cancer; and avoid doing harm to patients with low-risk cysts.