Head: prof dr Annemieke Smet
The mucin isoform landscape in barrier-related diseases
Loss of mucosal barrier integrity is a significant contributor in the pathophysiology of mucosal inflammatory diseases, but the role of transmembrane mucins, as epithelial signalling receptors mediating barrier dysfunction, is poorly understood. Upon inflammation, aberrantly expressed transmembrane mucins are likely to be the first point of contact between host tissue and the microbiota that penetrate the defective mucus layer and co-induce barrier dysfunction. Furthermore, the presence of genetic differences in mucin genes can give rise to a large repertoire of structurally diverse mucin mRNA isoforms via alternative splicing. While most isoforms encode similar biological functions, other have the potential to alter protein function resulting in progression towards disease. Currently, the mucin mRNA isoforms implicated in mucosal barrier dysfunction, is a scientific field to discover.
We recently designed a novel long-read mucin mRNA isoform sequencing approach allowing to unravel the complete mucin mRNA isoform landscape in a clinical sample (i.e. tissue specimens and blood samples). Therefore, our research focuses on 1) the discovery of the mucin mRNA isoform landscape, mediating mucosal barrier dysfunction in inflammatory bowel diseases (IBD), gastrointestinal cancers (GC and CRC) and respiratory tract infections (RVS, COPD, COVID-19) as well as 2) the different levels of regulation (i.e. microbial and inflammatory triggers) mediating alternative mucin splicing. We implement an unconventional approach encompassing a broadly applicable framework with next-generation sequencing tools, human sample collections and translational models. This work will lead to a new paradigm shift greatly advancing novel applications for disease follow-up at the level of the barrier function and pathology-specific targeting.
Technology Transfer Potential: patents in the domain of mucins
The first family (WO2021/013479) encompasses a series of claims covering MUC1 and MUC13 mRNA isoforms as biomarkers for the management of diseases characterized by mucosal barrier dysfunction. The second family (WO2022/003061) includes a series of claims covering the expression levels of mucins and their mRNA isoforms for use in diagnosis, monitoring, prevention and/or treatment of COVID-19. The third patent family (WO2021053238) protects the use of mucin mRNA expression by RSV-infected epithelial cells able to predict the severity of RSV infections in young children. The fourth patent family (EP23214719.9) encloses the intestinal mucin mRNA isoform landscape and the specific isoform panels that associate with inflammation, IBD subtype and anatomical location in the intestinal tract.
Mucin mRNA isoform-based service (MORSE) platform for the monitoring of barrier-related diseases (see also here)
Key Publications
Oosterlinck B, Ceuleers H, Arras W, De Man JG, Geboes K, De Schepper H, Peeters M, Lebeer S, Skieceviene J, Hold GL, Kupcinskas J, Link A, De Winter BY, Smet A. Mucin-microbiome sigantures shape the tumor microenvironment in gastric cancer. Microbiome, 2023, 11:86.
Video abstract: https://www.youtube.com/watch?v=SkblRy5eL-0
Breugelmans T, Arras W, Boen LE, Borms E, Kamperdijk L, de Man J, van de Vijver E, van Gils A, De Winter BY, Moes N, Smet A. Aberrant mucin expression profiles associate with pediatric inflammatory bowel disease presentation and activity. Inflamm Bowel Dis 2022 Oct 14:izac217.doi:10.1093/ibd/izac217.
Breugelmans T, Oosterlinck B, Arras W, Ceuleers H, De Man J, Hold G, De Winter BY, Smet A. The role of mucins in gastrointestinal barrier function in health and disease. Lancet Gastroenterology and Hepatology, 2022, 7(5):455-471.
Smet A, Breugelmans T, Michiels J, Lamote K, Arras W, De Man JG, Heyndrickx L, Hauner A, Huizing M, Malhotra-Kumar S, Lammens M, Hotterbeekx A, Kumar-Singh S, Verstraeten A, Loeys B, Verhoeven V, Jacobs R, Dams K, Coenen S, Ariën KK, Jorens PG, De Winter BY. A dynamic mucin mRNA signature associates with COVID-19 disease presentation and severity. JCI Insight, 2021, 6(19): e151777.
Breugelmans T, Van Spaendonk H, De Man JG, De Schepper HU, Jauregui-Amezaga A, Macken E, Linden SK, Pintelon I, Timmermans JP, De Winter BY, Smet A. In depth study of transmembrane mucins in association with intestinal barrier dysfunction during the course of T cell transfer and DSS-induced colitis. J Crohn’s & colitis, 2020, 14(7): 974-994.
PhDs
Baptiste Oosterlinck: Interaction between MUC13 signalling and mucosal microbiota in the development of gastric cancer
Wout Arras :A mucine-isoform based biomarker test for improved detection and treatment of IBD and gastrointestinal cancer
Nikita Hanning: Effect of modulation of the integrity of the intestinal barrier in irritable bowel syndrome - a translational approach
Kim Stobbelaar: Identification of host-virus interactions that contribute to immunopathology and severity of the disease in RSV infections in children
Hanne Voet: Impact of Chronic Obstructive Pulmonary Disease (COPD) severity and disease phenotypes on bronchial epithelial cell immune responses to (non-)infective triggers.