Skip to main content
European Commission logo
English English
CORDIS - EU research results
CORDIS
CORDIS Web 30th anniversary CORDIS Web 30th anniversary

Dissection of Glycan Function by Engineered Tissue Models

Periodic Reporting for period 4 - GlycoSkin (Dissection of Glycan Function by Engineered Tissue Models)

Reporting period: 2022-09-01 to 2023-11-30

Glycans decorate most proteins, cover cell membranes, and represent one of the four building blocks of life, together with nucleic acids, lipids, and amino acids. Yet, our understanding of how glycans influence the life of cells and organisms is limited, and only few functions have been molecularly dissected. Glycans present a huge structural diversity with species and cell- type specificity that underlie specific biological functions. However, more than half a century of research has been severely hampered by the complexity and technical difficulties with analyzing glycans. While, the glycome (all glycans in a cell or organism) is a difficult entry point for discovery, the glycogenome (all genes involved in glycosylation) in contrast is a feasible entry point, because most of the genes controlling glycosylation are now known, and there are fewer technical barriers especially with the emergence of gene editing technologies. Our research group has pioneered the “glycogenome entry” to functional glycomics using gene editing to simplify glycosylation in cells, and extended this strategy to develop a next generation approach using organotypic tissue models in combination with mass spectrometry to decipher glycan functions. The tissue model has provided the first evidence that aberrant glycosylation in cancer directly induce oncogenic features, and that glycosylation is essential for viral propagation. In this proposal, we have used a step-by-step genetic deconstruction of glycosylation capacities in organotypic tissue models for broad discovery and dissection of specific structure-function relationships driving normal epithelial formation, cancer transformation and interaction between the host and viruses (using herpes simplex as a model system).
We have greatly advanced our understanding of how glycans decorating the surface of human cells, protect and maintain the homeostasis of our epithelial tissues, such as skin. By tweaking the genetic blueprints of tissue models to turn off specific genes responsible for creating these sugars, we have uncovered exiting insights into the wide range of roles these molecules play. For example, our experiments show that certain glycan structures are essential for the skin to form properly and act as a barrier, while other glycans are essential for how cells migrate, and heal wounds. The glycans also help cells stick together and communicate with each other, which is vital for the healthy function of our epithelial tissues. This work, which involved cutting-edge techniques like CRISPR-Cas9 gene editing and 3D tissue models, highlights just how complex and crucial these sugar structures are. They are not just decorative, but key players in vital biological processes. Our findings, open new doors for exploring how cells communicate and how this knowledge can be applied, for example, to better understand diseases like cancer. Additionally, we have developed new methods to map out the sugar structures on cell surfaces, significantly advancing our ability to study how these molecules vary under both healthy and pathological conditions. In the context of viral infections, our findings have illuminated how glycans affcet viral infections. By examining skin cells genetically engineered to lack certain sugars, we've learned how different sugars can impact the stages of herpes virus infection. This not only adds a new layer to our understanding of viral infections but also showcases the power of genetic engineering in dissecting the complex interactions between viruses and their host cells. In summary, our research have found that cell surface glycans are far from simple decorations, but instead play fundamental roles in health, disease, and host-pathogen interactions.
We have developed a new way to study how different molecular structures affect cell-cell communication in tissue homeostasis that offers a significant advantage over traditional animal research. This method is not only more ethical and sustainable but also broadens access to human various tissue models for scientific exploration. Importantly, our strategy can be applied to virtually any type of tissue, paving the way for comprehensive studies across different organ systems. This innovation allows for the detailed examination of how indivdiual molecules or signalling pathways affect tissue generation and how sepcific disease processes affect tissue formation. In terms of therapeutic advancements, our research into the human glycome (the entire set of sugars in the body) and its role in maintaining tissue integrity has opened new avenues for targeting cancer. By analyzing how proteins are glycosylated (sugar-modified) in the human body, we have identified unique patterns associated with cancer cells. This led to the creation of monoclonal antibodies that are highly specific for proteins altered by cancer-related glycosylation changes. These antibodies have shown promising results in reducing tumor size in both our 3D models of human tissue and in animal models. Our findings have layed the foundation to novel cancer treatments focused on glycan (sugar molecule) alterations. In essence, our work is bridging the gap between sophisticated scientific research and practical medical applications, offering new hope for personalized and effective cancer therapies.
Overview of GlycoSkin program