Abstract 5728: Metabolomic pathway alterations in endometrial cancer
Authors: Altadill Tatiana 
Published: July 2017

Abstract
Introduction: Endometrial cancer is the most frequent gynecological cancer diagnosed in United States, accounting for 76,000 deaths every year. Up to now, it has been broadly described the proteomic and the transcriptomic profiles of endometrial cancer (EC). However, the metabolomic content of EC tissues is largely unknown. In this work, we aim to characterize the pathways dysregulated in EC tumorigenesis and the changes that the metabolites experience along the progression of the disease.
Methods: We performed an untargeted discovery using liquid chromatography coupled with electro-spray quadrupole time of flight mass spectrometry (UPLC-ESI-QTOF-MS). We analyzed the metabolomic and lipidomic profile of a set of 56 tumor tissues, corresponding to 39 different stages of endometrioid EC tumors (10 FIGO stages IA, 9 stages IB, 10 stages II and 10 stages III), and 17 benign endometrium tissues. Verification of initiation and progression markers was performed by MS/MS. Furthermore the dysregulated pathways were validated by Real Time quantitative PCR (RTqPCR) and Immunohistochemistry (IHQ) in an independent cohort of 60 and 109 patients, respectively.
Results: A total of 8,146 features were detected in the positive and 7,558 in the negative electrospray ionization mode. Among those, a list of 40 significant differentially expressed metabolites (FC&gt;2) was verified. The lipid metabolism appeared highly upregulated; with an important number of PCs, PSs, PEs, PIs and PGs. Linoleic acid, 3-Deoxyvitamin D3, and UDP-N-acetyl-D-galactosamine were also upregulated in EC. Differently, the peptide Glu Phe Arg Trp, some amides (palmitamide, stearamide and oleamide), PA (18:0/18:1), PE (20:1/22:6), PE (22:6/P-18:1), PG (19:0/22:4), inosine and picolinic acid were downregulated in the tumor tissue. Regarding tumoral progression, we showed a significant and non-gradual dysregulation of PC (16:0/20:5), the PC (16:0/22:6), PE (16:0/22:6), PE (22:6/P-18:1) and PE (18:1/22:6) at different stages of cancer progression. A significant decrease of the levels of UDP-N-acetyl-D-galactosamine and Arachidonic acid at advanced stages of the tumor was detected. We confirmed by RTqPCR and by IHQ the downregulation of the 3 adenosine-to-inosine editing enzymes (ADAR1, ADAR2 and ADARB3) in EC patients compared to the control group. We also observed a higher expression of the enzymes in the most aggressive (serous EC tumors) compared to the less aggressive tumors (endometrioid EC tumors). We are currently performing studies to understand the role of the RNA editing pathway in EC.
Conclusions: In this study we described the metabolome and lipidome of EC initiation and progression. We verified and validated several metabolites that are significantly differentially found in control subjects compared to EC patients and along tumoral progression. These results also depictured the metabolism of EC and deciphered, for the first time, an alteration in the adenosine-to-inosine editing pathway in EC.
Note: This abstract was not presented at the meeting.
Citation Format: Tatiana Altadill. Metabolomic pathway alterations in endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5728. doi:10.1158/1538-7445.AM2017-5728