Research Baptiste Oosterlinck

Abstract

Gastric cancer (GC) is the fifth most common cancer and the fourth leading cause of cancer-related death worldwide. Although Helicobacter pylori is the primary cause of GC, the disease is complex and involves multiple genetic, molecular, environmental, and microbiological factors. One of the hallmark features of gastric adenocarcinomas is aberrant mucin expression which drives tumorigenesis by influencing cellular growth and survival. Mucins are the gatekeepers of the mucus barrier covering the epithelium underneath and are heavily glycosylated. They are expressed at the apical surfaces of epithelial cells either as secretory or transmembrane mucins and play a crucial role in the maintenance of mucosal barrier homeostasis by communicating between the microbial flora and the mucosal immune system. Furthermore, these aberrantly expressed glycoproteins are also linked to the initiation, progression, and poor prognosis of GC. Of particular interest is the transmembrane 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. 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 in the gastric mucosa. Nevertheless, which specific tumour-enriched bacterial species can act as potential drivers in MUC13-mediated gastric carcinogenesis remains largely unknown. Therefore, this study aims to 1) identify the tumour-enriched bacterial taxa, other than H. pylori, involved in MUC13-driven gastric carcinogenesis and 2) unravel the MUC13-mediated mechanisms affecting tumour cell death.

Researcher(s)

• Promoter: Smet Annemieke
• Co-promoter: De Winter Benedicte
• Fellow: Oosterlinck Baptiste

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

The Laboratory of Experimental Medicine and Pediatrics - within the Faculty of Medicine and Health Sciences and closely linked to the Antwerp University Hospital - focusses its research on the study of inflammation in a clinically relevant context built on interdisciplinary methodologies and collaborations. To remain in the forefront of research we perform ground-breaking experimental, as well as clinical and translational research from bench to bedside and vice versa, using innovative and high-end methodologies including organoids, rodent models, cell cultures, different next-generation omics approaches and clinical trials. We challenge you to write down a project that will have an added value to one of the research lines currently explored at LEMP (www.uantwerpen.be/en/research-groups/lemp) and briefly described below. Loss of mucosal barrier integrity is a significant contributor in the pathophysiology of mucosal inflammatory/infectious diseases (e.g. IBD, gastrointestinal cancers, RSV, COVID-19). The role of transmembrane mucins, as epithelial signalling receptors mediating barrier dysfunction, is poorly understood. Furthermore, the presence of genetic differences in mucin genes can give rise via alternative splicing to a large repertoire of structurally diverse mucin mRNA isoforms encoding similar biological functions or altering protein function resulting in progression towards disease. Currently, the mucin mRNA isoform landscape implicated in mucosal barrier dysfunction is a field to discover. Volatile organic compounds (VOCs) are compounds that are by-products of cell metabolism and induced by inflammation. The human body houses thousands of VOCs which are exhaled and can serve as non-invasive markers for disease. Hence, breathomics is applied to search for clinically relevant diagnostic, prognostic and predictive biomarkers for inflammation-related diseases in adults and children (thoracic cancers, COVID-19, asthma, COPD, BPD in neonates, gastrointestinal diseases) and to monitor the effect of air pollution on human health. However, there is a need for further identification and data mining of volatiles, linking VOCs to metabolic processes. Chronic low-grade inflammation is a key factor in obesity. As its treatment remains challenging over all age groups, research focusses on new treatment strategies for obesity, that minimize dropout and weight regain. Pathophysiological processes (hypoxia) that lead to comorbidities like cardiovascular and metabolic morbidity and obstructive sleep apnoea are also of interest. Kidney transplantation is the best treatment for patients with end-stage renal disease. As diagnosis requires invasive procedures, there is a need of sensitive, non-invasive markers of an early-stage acute rejection and the early diagnosis of glomerular damage in children and adults with various underlying diseases (diabetes, obesity or sickle cell anaemia). Visceral pain is a key feature of the gastrointestinal disorders IBD and IBS. The management of visceral hypersensitivity is challenging and requires further research towards new treatment targets. Unravelling the immunopathogenesis of chronic Hepatitis B infections is essential in the quest for novel treatment approaches. While the ineffective T-cell responses are well-known, B cells have been left largely understudied, urging a deeper understanding of the role of the humoral immune response in chronic HBV at the level of HBV-specific antibody production and of the phenotypic/functional level of B cells. Non-Alcoholic Fatty Liver Disease (NAFLD) is the global leading cause of chronic liver disease but pharmacological treatment remains poorly successful. Changes in liver hemodynamics and in parenchymal oxygenation contribute to the steatohepatitis and progressive disease worsening and are a potential drugable target. Furthermore, the role of NAFLD on extrahepatic vascular alterations contributing to cardiovascular disease warrants further study.

Researcher(s)

• Promoter: De Winter Benedicte
• Co-promoter: Adomati Tom
• Co-promoter: Lamote Kevin
• Co-promoter: Ledeganck Kristien
• Co-promoter: Smet Annemieke
• Co-promoter: Van Eyck Annelies
• Fellow: Oosterlinck Baptiste

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

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.

Researcher(s)

• Promoter: Smet Annemieke
• Fellow: Oosterlinck Baptiste

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project