• Daniela Freitas, Diana Campos, Joana Gomes, Filipe Pinto, Joana A Macedo, Rita Matos, Stefan Mereiter, Marta T Pinto, António Polónia, Fátima Gartner, Ana Magalhães, and Celso A Reis.
• i3S-Institute for Research and Innovation in Health, University of Porto, Rua Alfredo Allen 208, Porto 4200-135, Portugal; IPATIMUP -Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr. Roberto Frias s/n, Porto 4200-465, Portugal; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira n.228, Porto 4050-313, Portugal.
• EBioMedicine. 2019 Feb 1; 40: 349-362.

BackgroundChanges in glycosylation are known to play critical roles during gastric carcinogenesis. Expression of truncated O-glycans, such as the Sialyl-Tn (STn) antigen, is a common feature shared by many cancers and is associated with cancer aggressiveness and poor-prognosis.MethodsGlycoengineered cell lines were used to evaluate the impact of truncated O-glycans in cancer cell biology using in vitro functional assays, transcriptomic analysis and in vivo models. Tumor patients 'samples and datasets were used for clinical translational significance evaluation.FindingsIn the present study, we demonstrated that gastric cancer cells expressing truncated O-glycans display major phenotypic alterations associated with higher cell motility and cell invasion. Noteworthy, the glycoengineered cancer cells overexpressing STn resulted in tumor xenografts with less cohesive features which had a critical impact on mice survival. Furthermore, truncation of O-glycans induced activation of EGFR and ErbB2 receptors and a transcriptomic signature switch of gastric cancer cells. The disclosed top activated genes were further validated in gastric tumors, revealing that SRPX2 and RUNX1 are concomitantly overexpressed in gastric carcinomas and its expression is associated with patients' poor-survival, highlighting their prognosis potential in clinical practice.InterpretationThis study discloses novel molecular links between O-glycans truncation frequently observed in cancer and key cellular regulators with major impact in tumor progression and patients' clinical outcome.Copyright © 2019. Published by Elsevier B.V.

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