3D glyco-engineered models to address the role of glycosylation in gastric cancer clinical management

ended

Gastric cancer is an important health problem, being the fifth most common cancer and the third leading cause of cancer death. Its late diagnosis accompanied with a bad prognosis keeps this malignancy among the most deadly. After generations of cancer therapy based on chemical drugs causing severe side effects and limited efficiency, cancer treatment undergoes a paradigm shift towards targeted therapy, employing both monoclonal antibodies and small molecule inhibitors of receptor tyrosine kinase activity, as the most promising tool for the years to come. However, there are numerous patients that do not respond to these novel treatments due to mutations in downstream signalling pathways or to undefined molecular mechanisms. Protein glycosylation has been shown to modulate cellular receptor functions and alter antibody binding affinities and therefore foreshadows to play a major role in cancer therapy resistance. The GlycoModels project aims to identify glycan alterations on cell receptors that lead to targeted therapy resistance of gastric tumours. Using cutting-edge gene editing techniques, gastric cancer cell lines will be glyco-engineered to express hallmark glycan epitopes and applied in 3D-culture systems as advanced models mimicking the tumour microenvironment. These 3D-GlycoModels will display differential response to treatment with the most promising targeted therapy agents for key cell receptors (HER2, VEGFR, MET and RON) involved in growth, progression, and spread of cancer. In-depth analysis of the GlycoModels, covering glycan characterisation of the cell receptors, disclosing activated signalling pathways, and transcriptomics will unveil our understanding on driving mechanisms in therapy resistance and the glycosylation patterns involved. The structural validation of these glycoforms in human samples will deliver new biomarkers to be used in personalised therapy selection and thus, improve the outcome of advanced gastric cancer patients.