Metabolomic study for the identification of diagnostic markers and the characterization of the dissemination process of endometrial cancer

Resumen

Endometrial cancer (EC) is the most common gynaecological malignancy in developed countries and the fourth most common cancer in women. It shows a continuous increasing incidence among younger patients. Concerning this problematic, many new research lines focused on the better understanding of the molecular and metabolic changes associated to EC have appeared the last decades. Moreover, an easy, quick, applicable and specific technique in order to properly diagnose EC and discriminate EC form other similar malignancies is urgently needed. For this purpose, several studies carried out during the last years based their efforts in the research for new biotechnological methods with the idea of identifying novel tumoral biomarkers in order to improve EC diagnosis, staging, prognosis and therapeutic response. In order to overcome the exposed clinical challenges, the major goal of this thesis work was to identify a novel panel of EC diagnostic markers and to gain insights into altered metabolic pathways in the establishment and dissemination process of EC using metabolomic-based approaches in order to improve patient care and overcome the mortality rate of this malignancy. To achieve this objective, we divided the thesis work into three chapters each one of them associated to a specific objective: 1) Optimization of the extraction methods for the metabolomic analysis of human biofluids including extracellular vesicles (EVs) using liquid chromatography mass spectrometry (LC-MS) techniques; 2) Identification, verification and validation of EC diagnostic markers from human biofluids (use of plasma, uterine aspirates and EVs isolated from both biofluids); 3) Metabolomic study of EC regarding the process of dissemination in tissues. As a result of the dissertation, we describe standardized approaches for MS based metabolomics profiling of extracellular vesicles (EVs) that can be translated to other biomarker research lines and may have big impact in translational clinics and improving the outcome of EC patients. We also present evidence that the enriched cargo contained in EVs offers new opportunities for the discovery of low abundant metabolites as disease biomarkers. Importantly, we highlighted the relevance of the use of proximal biofluids, specifically UA, and EVs in the biomarker research and we opened a new avenue for identification of more specific EC markers. Moreover, the data presented in this dissertation depicts a significant advance in the understanding of the metabolic alterations that take place in EC tumorogenesis. Our results and in vitro models evidenced the oncogenic role of ADAR2 in EC.