Multilevel Plasticity and Altered Glycosylation Drive Aggressiveness in Hypoxic and Glucose-Deprived Bladder Cancer Cells

ABSTRACT: Bladder tumours with aggressive characteristics often inhabit microenvironmental niches marked by low oxygen levels (hypoxia) and limited glucose supply due to inadequate vascularization. The molecular mechanisms facilitating cellular adaptation to these stimuli remain largely elusive. Employing a multi-omics approach, we discovered that hypoxic and glucose-deprived cancer cells enter a quiescent state supported by mitophagy, fatty acid β-oxidation, and amino acid catabolism, concurrently enhancing their invasive capabilities remarkably. Reoxygenation and glucose restoration efficiently reversed cell dormancy without affecting cellular viability, highlighting significant molecular plasticity in adapting to microenvironmental cues. Furthermore, cancer cells exhibited substantial perturbation of protein O-glycosylation, leading to simplified glycophenotypes with shorter glycosidic chains. Exploiting glycoengineered cell models, we established that immature glycosylation contributes to reduced cell proliferation and increased invasion. Our findings collectively indicate that hypoxia and glucose deprivation trigger cancer aggressiveness, reflecting an adaptive escape mechanism underpinned by altered metabolism and protein glycosylation. Building on these data, we have performed on a phosphoproteomics characterization of hypoxic and glucose-deprived bladder cancer cell lines, aiming to gain a deeper understanding of the signaling rewiring experienced by cancer cells under microenvironmental stress and to identify potential targets for future clinical intervention.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Bladder Cell, Bladder, Cell Culture

DISEASE(S): Urinary Bladder Cancer

SUBMITTER: Tim Veth  

LAB HEAD: José Alexandre Ferreira

PROVIDER: PXD045777 | Pride | 2024-03-27

REPOSITORIES: Pride