Investigating Complex Crosstalk in the Pancreatic Cancer Microenvironment

Pancreatic cancer has a very low survival rate and better treatments are urgently needed. In pancreatic cancer up to 90% of the tumour can be made up of 'normal cells' like immune cells and wound healing cells called fibroblasts. These cells get 'hijacked' by the tumour to help the tumour grow and to protect it from drugs and anti-tumour immune cells. This tumour environment, known as the stroma, can also be affected by certain treatments. Although we know quite a lot about what has gone wrong in the cancer cells, we understand far less about how the cells in the stroma become altered, and how they communicate with each other to help the tumour grow and protect itself from therapies. Recently the situation has become more complex, with the discovery that these immune cells and fibroblasts come in different flavours, some of which help the tumour, but some of which might actually act to fight the tumour. We have also identified that a very rare type of immune cell, called a gamma delta T cell, might control how these different flavours of cell evolve. We also know that some treatments, particularly radiotherapy, can cause changes in these stromal cells, and potentially drive them to further support tumour growth and resistance to therapy. Therefore it's important that we investigate the signals coming from these cells and understand how they can promote tumour growth, so that we can target them with therapies. We aim to answer some key questions about pancreatic cancer biology so that we can identify new treatments. Specifically, we want to investigate how the stromal immune cells and fibroblasts communicate with each other to promote tumour growth, how the gamma delta T cells can alter the flavour of these stromal cells, how radiotherapy can make the stromal cells even more tumour-supportive, and how we might prevent it. We will be using a combination of cutting edge techniques: state-of-the-art mouse models that develop pancreatic tumours very similar to human tumours, a mouse radiotherapy system that allows us to treat the tumours while minimising damage to surrounding healthy tissue similar to radiotherapy techniques used for patients, a technique called spatial transcriptomics, which allows us to see a genetic 'blueprint' of every cell in a slice of tumour so we can map signals precisely to individual cell types, and a technique called single-cell RNA sequencing, which allows us to investigate thousands of changes in each individual cell in a tumour. The most exciting changes that hint at new therapeutic strategies will be investigated in human tumours, and ultimately tested in models.