Over the past 30 years, there has been a remarkable increase in cancer survival rates across many cancer types. Unfortunately, these changes have not translated significantly to gastric cancer survival, as it remains one of the leading causes of cancer related mortality worldwide. The development and progression of gastric cancer is a complicated process involving poorly understood interactions between many different cell types.
The aims of this project are to gain an increased understanding of the initiation, development and progression of gastric tumours. Using immunohistochemistry and flow cytometry we have found that there is a significant increase in the numbers of epithelial tuft cells, a rare chemosensory cell population, within the cancers of the mouse stomach. This is most noticeable within the tumours proper, with high numbers of these cells expressing doublecortin like kinase 1 (DCLK1), a marker that is linked to both tuft cells and tumour stem cells.
We propose that the tuft cell population present throughout the gastrointestinal system and type 2 innate lymphoid cells (ILC2), a member of a recently discovered immune cell population, found predominantly at mucosal surfaces, contribute significantly to the development of gastric cancer. Tuft cells and ILC2s together form a positive feed forward loop, that when excessively activated alter gastric homeostasis to promote metaplasia and eventually lead to the formation of gastric cancer. Genetic ablation of tuft cells results in a significant reduction in tumour weight within our mouse model of gastric cancer, underscoring the importance of this cell population within the tumour microenvironment.
Using various reporter and deleter mouse strains, we are aiming to characterise the interactions between tuft cells and ILC2 during homeostasis, as well as during tumour initiation and progression within stomach. Using this information, we will look at inhibiting key pathways of the Tuft cell/ILC2 axis to reduce tumour burden or inhibit tumour development.