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

Abstract

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. Its diagnosis relies on the evaluation of an endometrial biopsy, which is a minimally-invasive method. Moreover, the management of patients is based on the assessment of the clinic-pathological features of the tumor, which is not completely accurate since some cases still recur unpredictably. In order to overcome the existing 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 that are concomitant with the establishment and dissemination process of EC. We achieved our goal by using metabolomic-based approaches to finally improve patient care and overcome the mortality rate of this malignancy. To reach these objectives, we divided the thesis work into three chapters each one of them addressing a specific objective: 1) Optimization of the extraction methods for the metabolomic analysis of extracellular vesicles (EVs) contained in biofluids 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 profiling of EC tissues to elucidate the molecular alterations that take place in the initiation and progression of the disease. As main findings of the dissertation, we describe standardized approaches for MS based metabolomics profiling of extracellular vesicles 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 abundance metabolites as disease biomarkers. Importantly, we highlight 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 biomarkers. 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 and thus the role of RNA editing pathway in EC. Taken together, these studies help further the field of EC research by demonstrated use and optimization of new methodologies (EVs metabolomics) and gaining insights into specific biochemical perturbations that may have a critical role in endometrial carcinogenesis.

Date of Award	6 Feb 2018
Original language	English
Supervisor	Eva Colas Ortega (Director), Antonio Gil Moreno (Director) & Rosa Miro Ametller (Tutor)