Metabolomics, Transcriptomics and Functional Glycomics Reveals Bladder Cancer Cells Plasticity and Enhanced Aggressiveness Facing Hypoxia and Glucose Deprivation

• DOI: 10.1101/2021.02.14.431133
• Publication Date: 2021-02-15T06:25:22Z
• Authors: Andreia Peixoto; Rui Freitas; Dylan Ferreira; Marta Relvas-Santos; Paula Paulo; Marta Cardoso; Janine Soares; Cristiana Gaiteiro; Carlos Palmeira; Filipe Teixeira; Rita Ferreira; Maria José Oliveira; André M. N. Silva; Lúcio Lara Santos; José Alexandre Fe...
• Keywords: Glycomics; Hypoxia; Anaerobic glycolysis

Abstract Bladder cancer constitutes one of the deadliest genitourinary diseases, especially when diagnosed at late stages. These tumours harbour microenvironmental niches characterized by low levels oxygen (hypoxia) and limited glucose supply due to poor vascularization. However, synergic contribution these features disease development is poorly understood. Here, we demonstrated that cells with distinct histopathological molecular backgrounds responded similarly such stimuli. Cancer arrested proliferation, significantly increased invasive capacity in vitro enhanced tolerance cisplatin-based chemotherapy. Reoxygenation access restored basal proliferation invasion without triggering stress-induced apoptosis, denoting significant cellular plasticity adapting cues. Whole transcriptomics showed major reprogramming, supporting main functional alterations. Metabolomics evidenced fatty acids β -oxidation as bioenergetic pathway rather than anaerobic glycolysis generally adopted hypoxic cells. Joint analysis also suggested relevant alterations mucin-type O -glycan biosynthesis. Glycomics confirmed a antagonization -glycosylation pathways, leading simple cell glycophenotypes accumulation immature short-chain -glycans Tn STn antigens surface. Glycoengineered models reflecting were developed studies vivo overexpression decreased promoted chemoresistance, reinforcing their close link tumour aggressiveness. Collectively, have hypoxia deprivation trigger more aggressive behaviours, what appears be an escape mechanism from stress. We propose that, altered glycosylation may used target subpopulations, paving way for precision oncology.