Multilevel plasticity and altered glycosylation drive aggressiveness in hypoxic and glucose-deprived bladder cancer cells
Summary: Bladder tumors with aggressive characteristics often present 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. Emplo...
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Elsevier
2025-02-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225000173 |
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| author | Andreia Peixoto Dylan Ferreira Andreia Miranda Marta Relvas-Santos Rui Freitas Tim S. Veth Andreia Brandão Eduardo Ferreira Paula Paulo Marta Cardoso Cristiana Gaiteiro Sofia Cotton Janine Soares Luís Lima Filipe Teixeira Rita Ferreira Carlos Palmeira Albert J.R. Heck Maria José Oliveira André M.N. Silva Lúcio Lara Santos José Alexandre Ferreira |
| author_facet | Andreia Peixoto Dylan Ferreira Andreia Miranda Marta Relvas-Santos Rui Freitas Tim S. Veth Andreia Brandão Eduardo Ferreira Paula Paulo Marta Cardoso Cristiana Gaiteiro Sofia Cotton Janine Soares Luís Lima Filipe Teixeira Rita Ferreira Carlos Palmeira Albert J.R. Heck Maria José Oliveira André M.N. Silva Lúcio Lara Santos José Alexandre Ferreira |
| author_sort | Andreia Peixoto |
| collection | DOAJ |
| description | Summary: Bladder tumors with aggressive characteristics often present 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. |
| format | Article |
| id | doaj-art-f6e3e482bdff4e1e8164ae7eaf781d3b |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-f6e3e482bdff4e1e8164ae7eaf781d3b2025-01-22T05:43:08ZengElsevieriScience2589-00422025-02-01282111758Multilevel plasticity and altered glycosylation drive aggressiveness in hypoxic and glucose-deprived bladder cancer cellsAndreia Peixoto0Dylan Ferreira1Andreia Miranda2Marta Relvas-Santos3Rui Freitas4Tim S. Veth5Andreia Brandão6Eduardo Ferreira7Paula Paulo8Marta Cardoso9Cristiana Gaiteiro10Sofia Cotton11Janine Soares12Luís Lima13Filipe Teixeira14Rita Ferreira15Carlos Palmeira16Albert J.R. Heck17Maria José Oliveira18André M.N. Silva19Lúcio Lara Santos20José Alexandre Ferreira21Research Center of IPO-Porto (CI-IPOP) / CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto) / Porto Comprehensive Cancer Center (P.ccc) Raquel Seruca, Porto, Portugal; i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, PortugalResearch Center of IPO-Porto (CI-IPOP) / CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto) / Porto Comprehensive Cancer Center (P.ccc) Raquel Seruca, Porto, Portugal; i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, PortugalResearch Center of IPO-Porto (CI-IPOP) / CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto) / Porto Comprehensive Cancer Center (P.ccc) Raquel Seruca, Porto, Portugal; i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, PortugalResearch Center of IPO-Porto (CI-IPOP) / CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto) / Porto Comprehensive Cancer Center (P.ccc) Raquel Seruca, Porto, Portugal; i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal; LAQV-REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, PortugalResearch Center of IPO-Porto (CI-IPOP) / CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto) / Porto Comprehensive Cancer Center (P.ccc) Raquel Seruca, Porto, Portugal; i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, PortugalBiomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Utrecht, the Netherlands; Netherlands Proteomics Center, Padualaan, Utrecht, the NetherlandsResearch Center of IPO-Porto (CI-IPOP) / CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto) / Porto Comprehensive Cancer Center (P.ccc) Raquel Seruca, Porto, PortugalResearch Center of IPO-Porto (CI-IPOP) / CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto) / Porto Comprehensive Cancer Center (P.ccc) Raquel Seruca, Porto, PortugalResearch Center of IPO-Porto (CI-IPOP) / CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto) / Porto Comprehensive Cancer Center (P.ccc) Raquel Seruca, Porto, PortugalResearch Center of IPO-Porto (CI-IPOP) / CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto) / Porto Comprehensive Cancer Center (P.ccc) Raquel Seruca, Porto, PortugalResearch Center of IPO-Porto (CI-IPOP) / CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto) / Porto Comprehensive Cancer Center (P.ccc) Raquel Seruca, Porto, Portugal; School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, PortugalResearch Center of IPO-Porto (CI-IPOP) / CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto) / Porto Comprehensive Cancer Center (P.ccc) Raquel Seruca, Porto, Portugal; School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, PortugalResearch Center of IPO-Porto (CI-IPOP) / CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto) / Porto Comprehensive Cancer Center (P.ccc) Raquel Seruca, Porto, Portugal; School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal; QOPNA & LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro, PortugalResearch Center of IPO-Porto (CI-IPOP) / CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto) / Porto Comprehensive Cancer Center (P.ccc) Raquel Seruca, Porto, PortugalCentre of Chemistry, University of Minho, Braga, PortugalQOPNA & LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro, PortugalResearch Center of IPO-Porto (CI-IPOP) / CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto) / Porto Comprehensive Cancer Center (P.ccc) Raquel Seruca, Porto, Portugal; Department of Immunology, Portuguese Oncology Institute of Porto, Porto, Portugal; Health School of University Fernando Pessoa, Porto, PortugalBiomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Utrecht, the Netherlands; Netherlands Proteomics Center, Padualaan, Utrecht, the Netherlandsi3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, PortugalLAQV-REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, PortugalResearch Center of IPO-Porto (CI-IPOP) / CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto) / Porto Comprehensive Cancer Center (P.ccc) Raquel Seruca, Porto, Portugal; Health School of University Fernando Pessoa, Porto, Portugal; Department of Surgical Oncology, Portuguese Oncology Institute of Porto, Porto, PortugalResearch Center of IPO-Porto (CI-IPOP) / CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto) / Porto Comprehensive Cancer Center (P.ccc) Raquel Seruca, Porto, Portugal; School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal; Corresponding authorSummary: Bladder tumors with aggressive characteristics often present 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.http://www.sciencedirect.com/science/article/pii/S2589004225000173Health sciencesMedicineMedical specialtyInternal medicineOncologyNatural sciences |
| spellingShingle | Andreia Peixoto Dylan Ferreira Andreia Miranda Marta Relvas-Santos Rui Freitas Tim S. Veth Andreia Brandão Eduardo Ferreira Paula Paulo Marta Cardoso Cristiana Gaiteiro Sofia Cotton Janine Soares Luís Lima Filipe Teixeira Rita Ferreira Carlos Palmeira Albert J.R. Heck Maria José Oliveira André M.N. Silva Lúcio Lara Santos José Alexandre Ferreira Multilevel plasticity and altered glycosylation drive aggressiveness in hypoxic and glucose-deprived bladder cancer cells iScience Health sciences Medicine Medical specialty Internal medicine Oncology Natural sciences |
| title | Multilevel plasticity and altered glycosylation drive aggressiveness in hypoxic and glucose-deprived bladder cancer cells |
| title_full | Multilevel plasticity and altered glycosylation drive aggressiveness in hypoxic and glucose-deprived bladder cancer cells |
| title_fullStr | Multilevel plasticity and altered glycosylation drive aggressiveness in hypoxic and glucose-deprived bladder cancer cells |
| title_full_unstemmed | Multilevel plasticity and altered glycosylation drive aggressiveness in hypoxic and glucose-deprived bladder cancer cells |
| title_short | Multilevel plasticity and altered glycosylation drive aggressiveness in hypoxic and glucose-deprived bladder cancer cells |
| title_sort | multilevel plasticity and altered glycosylation drive aggressiveness in hypoxic and glucose deprived bladder cancer cells |
| topic | Health sciences Medicine Medical specialty Internal medicine Oncology Natural sciences |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225000173 |
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