Background: Global Observatory Database ranked Gastric cancer as 5th in both incidence and mortality rate worldwide as of 2022. Contributing to this trend are early GC being asymptomatic and a lack of targets at advanced stages. Tuft cells in the gut epithelial layer stimulate group 2 innate lymphoid cells (ILC2s) by secreting IL25 cytokine, which in turn, secretes IL13 that induces tuft cell proliferation in gut. Our lab has shown that excessive activation of the tuft cell/ILC2 signalling circuit leads to the accumulation of an inflammatory ILC2 subtype (iILC2) which promotes tumour. Nevertheless, it remains unclear whether tuft cells and iILC2s are required for metastatic spread and/or growth.
Aims: To dissect the role of tuft cell and (i)ILC2 in advanced gastric cancer and metastasis.
Methods: We have used our in-house preclinical mouse model of metastatic GC to generate tissue samples of GC and liver metastases. Multiplex OPAL staining was performed to detect tuft cells and ILC2s in primary and metastatic tumour tissues. Tumour burden is compared between wildtype and ILC2KO GC models.
Results: Multiplex staining revealed the presence of tuft cells in metastatic tumour sites. We observed Pou2f3 positive cells, although some of these cells did not express DCLK1, a marker for differentiated tuft cells. These Pou2f3 positive cells have the potential to differentiate into tuft cells under specific tumour microenvironment conditions. Dclk1 & Pou2f3 positive tuft cells were also present in the primary tumour. ILC2 staining revealed inflammatory ILC2s in the stomach. Differences in primary tumour growth were observed between wildtype and ILC2KO GC models.
Conclusions: Tuft cells and (i)ILC2s are present in the primary tumour site and in liver metastases. Moreover, primary GC growth is reduced in mice lacking ILC2s. Together, these results support our hypothesis that tuft cell/ILC2 signalling contributes to primary and metastatic tumour growth.