Crosstalk between MUC13 signalling and the mucosal microbiota in gastric cancer development.

Chronic infection with the human pathogen Helicobacter pylori plays a crucial role in the initial steps of gastric cancer (GC) development by causing enhanced inflammation and progressive changes in the gastric mucosa, like alterations in mucin expression and distribution. Aberrant expression of transmembrane mucins (MUCs) has been linked to the initiation, progression and poor prognosis of GC. Of particular interest is the MUC13 mucin. In healthy human beings, MUC13 is predominantly expressed in the intestines with only a very low level of expression in the stomach. In the diseased stomach, however, MUC13 expression is significantly upregulated by IL-1β (a key mediator in Helicobacter-related GC) and more specifically in adenocarcinoma and during the early events of the carcinogenesis process. Furthermore, MUC13 contains serine and tyrosine residues for potential phosphorylation and a protein kinase C consensus phosphorylation motif in its cytoplasmic domain that could play a critical role in tumorigenesis via cell signalling pathways that protect tumour cells from death. Currently, the exact role of MUC13 in the gastric carcinogenesis process remains poorly understood. Therefore, in the first part of this project (work package 1 (WP1)), we will investigate the role of IL-1β-induced MUC13 expression in different modes of programmed cell death (including apoptosis, necroptosis, pyroptosis and ferroptosis) and autophagy (as a form of cell survival) in GC cells and identify its downstream intracellular mechanism involved using in vitro, in vivo and translational approaches. In addition, we will also verify whether cell death resistance mediated by MUC13 already occurs in gastric pre-neoplastic lesions (i.e. atrophy and intestinal metaplasia). From a certain point on, however, development of gastric adenocarcinoma may be H. pylori independent, since colonization decreases in later steps of carcinogenesis, particularly in patients who develop intestinal metaplasia and dysplasia, and is finally lost in adenocarcinoma. Nowadays, the gastric microbiome is believed to contribute to cancer progression as well. The GC microbiome seems to be enriched with intestinal or oral taxa which can be assigned to an increase in pH, caused by H. pylori, and to specific interactions of the microbiota with the gastric mucosa. More specifically, the carbohydrate structures present on mucins, like MUC13, can act as binding sites or metabolic substrates for bacteria and the abundancy of MUC13 plays thus an important determinant in the site-specific colonization of bacteria along the gastrointestinal tract. Nevertheless, which specific tumour-enriched bacterial species can act as potential drivers in MUC13-mediated gastric carcinogenesis remains largely unknown. Here (WP2), we will identify which tumour-enriched bacterial taxa other than H. pylori are associated with aberrant MUC13 expression during the gastric disease process and are thus involved in MUC13-mediated gastric cancer development. To approach this, 16s rRNA sequencing will be used to identify potential candidate species which will be further investigated in a germ free mouse model.

Keywords:MOUSE MODELS, GASTRIC DISORDERS, CANCER RESEARCH, BACTERIOLOGY

Disciplines:Gastro-enterology, Bacteriology, Cell death, Cell signalling, Cancer biology