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Aberrantly Glycosylated GLUT1 as a Poor Prognosis Marker in Aggressive Bladder Cancer
Eduardo Ferreira1,2, Dylan Ferreira1,2,3,4,5, Marta Relvas-Santos1,2,3,4,5,6
1Experimental Pathology and Therapeutics Group, Research Center of IPO-Porto (CI-IPOP), 4200-072 Porto, Portugal.
Abstract:
Muscle-invasive bladder cancer (MIBC) remains a pressing health concern due to conventional treatment failure and significant molecular heterogeneity, hampering the development of novel targeted therapeutics. In our quest for novel targetable markers, recent glycoproteomics and bioinformatics data have pinpointed (glucose transporter 1) GLUT1 as a potential biomarker due to its increased expression in tumours compared to healthy tissues. This study explores this hypothesis in more detail, with emphasis on GLUT1 glycosylation patterns and cancer specificity. Immunohistochemistry analysis across a diverse set of human bladder tumours representing all disease stages revealed increasing GLUT1 expression with lesion severity, extending to metastasis, while remaining undetectable in healthy urothelium. In line with this, GLUT1 emerged as a marker of reduced overall survival. Revisiting nanoLC-EThcD-MS/MS data targeting immature O-glycosylation on muscle-invasive tumours identified GLUT1 as a carrier of short glycosylation associated with invasive disease. Precise glycosite mapping uncovered significant heterogeneity between patient samples, but also common glycopatterns that could provide the molecular basis for targeted solutions. Immature O-glycosylation conferred cancer specificity to GLUT1, laying the molecular groundwork for enhanced targeted therapeutics in bladder cancer. Future studies should focus on a comprehensive mapping of GLUT1 glycosites for highly specific cancer-targeted therapy development for bladder cancer.
Insights
Glucose transporter 1 (GLUT1) is increasingly expressed in bladder tumors, correlating with disease severity and reduced survival. Specific immature glycosylation patterns on GLUT1 offer cancer specificity for targeted bladder cancer therapeutics.
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- Muscle-invasive bladder cancer (MIBC) presents significant treatment challenges due to heterogeneity.
- Identifying novel biomarkers is crucial for developing targeted therapies for MIBC.
- Glucose transporter 1 (GLUT1) has emerged as a potential biomarker with increased expression in tumors.
Purpose of the Study:
- To investigate GLUT1 expression patterns in bladder cancer.
- To analyze GLUT1 glycosylation in relation to cancer specificity and disease stage.
- To explore GLUT1 as a target for novel bladder cancer therapeutics.
Main Methods:
- Immunohistochemistry was used to assess GLUT1 expression across various bladder tumor stages.
- Nano liquid chromatography-electrospray ionization-tandem mass spectrometry (nanoLC-EThcD-MS/MS) analyzed O-glycosylation patterns.
- Glycosite mapping was performed on identified GLUT1 glycoforms.
Main Results:
- GLUT1 expression increases with bladder tumor severity, from early lesions to metastasis.
- GLUT1 is undetectable in healthy urothelium, indicating cancer specificity.
- Immature O-glycosylation on GLUT1 is associated with invasive bladder cancer and patient survival.
- Heterogeneity in glycosylation was observed, alongside common glycopatterns.
Conclusions:
- GLUT1 is a promising biomarker for bladder cancer progression and prognosis.
- Specific immature glycosylation patterns on GLUT1 confer cancer specificity.
- Targeting GLUT1 glycosylation presents a potential strategy for developing novel, specific bladder cancer therapies.
