Sinalização de uma assinatura metabólica circulante associada a glicosilação aberrante do tumor para gestão da caquexia em pacientes com cancro gástrico

Cancer cachexia affects 80% of patients with advanced cancer, and it critically compromises their well-being and survival2. Therefore, REBALNCE project addresses an IMPORTANT CHALLENGE as it proposes to early detect GC patients at risk of developing cachexia and to decipher potential targets to prevent or attenuate cancer cachexia evolution (project workflow attached). Importantly, the role of glycans has never been addressed in this process, which highlights the NOVELTY of this project. Moreover, the proposed project involves a diverse team of professionals ACROSS DIFFERENT DISCIPLINES including medical doctors, cancer scientists, analytical researchers, and computational data analysis experts. Therefore, we have designed the following SPECIFIC AIMS: 1- To early detect gastric cancer (GC) patients at risk of developing cachexia The 1st phase of the REBALANCE project will concentrate on the analysis of patient data and sample manipulation. Specifically, each patient will receive a nutritional and cachexia score at various stages of the disease. Moreover, we will examine the correlation between treatment efficacy, patient survival, and these nutritional and cachexia scores. Subsequently, we will conduct proteomic, metabolomic, and lipidomic analyses of gastric cancer (GC) plasma and their isolated extracellular vesicles (EVs) over time. Patients will also undergo screening for STn status, dividing them into STn+ and STn- GC patients. By employing digital health analysis techniques, we will identify metabolic patterns or signatures unique to each patient group over time. Following diagnosis, the identification of a distinct metabolic signature in samples from STn+ GC patients who develop cancer cachexia can aid in their early identification. Additionally, we can assess changes in the metabolic signature with treatment and evaluate whether cancer patients who eventually develop cancer cachexia benefit from current chemotherapy regimens in practice. 1) To decipher potential targets for preventing or attenuating gastric cancer cachexia evolution The second part of REBALANCE project will tackle the interplay between STn+ tumours and EVs and adipose tissue in a multidisciplinary approach involving the use of blood-plasma samples, organoids and mouse models. First, the transcriptomic and metabolic alterations induced by STn+ tumours and EVs in adipose tissue will be characterized. This will corroborate that STn+ tumours are responsible for the aberrant cachectic-like metabolic signature identified in GC patients. Furthermore, it will be possible to unravel novel potential targets to block adipose tissue remodelling. Then, STn+ tumours and EVs will be enzymatically targeted for STn removal to evaluate if cancer cachexia can be either delayed or attenuated in pre-clinical mouse models. Altogether, REBALANCE project has a tremendous potential for APPLICATION into the clinical routine to early identify and better stratify GC cachectic patients and to be further industrially explored for the development of novel therapeutic interventions to target the metabolic imbalance of cancer patients based on their glycosylation status.