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

Abstract

Bladder tumours with aggressive characteristics often present with 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. Reoxygenation and glucose restoration efficiently reversed cell quiescence without affecting cellular viability, highlighting significant molecular plasticity in adapting to microenvironmental challenges. 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, providing grounds for clinical intervention.

Stool Glycoproteomics Signatures of Pre-Cancerous Lesions and Colorectal Cancer

“…After deparaffinization, rehydration, and antigen retrieval, they were incubated with FITC-labeled PNA lectin (1:1000; Vector Laboratories, Newark, CA, USA) for 1 h at room temperature (RT). T24 WT cells were used as negative controls, whereas T-antigen-positive T24 GCNT1 KO cells were used as positive controls [60]. 4 ′ ,6 ′ -diamidino-2-phenylindole dihydrochloride (DAPI, 2.3 × 10 −3 µg/µL; Thermo Scientific, Waltham, MA, USA) was used as nuclear counterstain.…”