P01.23.a Cadherin-3-mediated Metabolic Reprogramming and Prognostic Stratification in Glioblastoma
Year: 2025
Type: conference-abstract
Abstract: BACKGROUND Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Cadherin-3 (or P-cadherin) is a cell adhesion molecule encoded by the CDH3 gene, which we previously identified as a key contributor to GBM aggressiveness. Despite its functional effects, the underlying mechanisms through which Cadherin-3 affects GBM remain unclear. This study aims to elucidate the molecular, cellular, and metabolic processes mediated by CDH3 that drive GBM. MATERIAL AND METHODS RNA sequencing was performed in two GBM models, including a patient-derived culture and a cell line, genetically manipulated to express differential levels of CDH3. Metabolic profiling was conducted via Seahorse analyses and extracellular glucose and lactate quantifications by HPLC. Lactate levels were further measured in the interstitial fluid of subcutaneous xenograft tumors. Protein expression of metabolism-associated markers was evaluated through western blot and immunohistochemistry in GBM cells and in in vivo tumors. The Cancer Genome Atlas (TCGA) data was used to study correlations between CDH3 and metabolic gene signatures, and associations with patient survival. RESULTS Transcriptomic analyses revealed that CDH3 expression is associated with multiple oncogenic pathways, including those related to metabolism. Findings from independent GBM cell models indicate that Cadherin-3 influences energy metabolism in a cell context-dependent manner, affecting the balance between glycolysis and oxidative phosphorylation. In GBM patient samples, CDH3 expression is positively correlated with glycolytic/plurimetabolic (GPM)-related genes, and inversely correlated with mitochondrial (MTC) signature genes. Notably, high CDH3 expression combined with the GPM signature defines a subgroup of patients with particularly poor survival outcomes. CONCLUSION These findings suggest Cadherin-3 as a key regulator of GBM metabolism, shaping distinct energetic profiles depending on the cellular context. Furthermore, its association with the GPM signature identifies a subset of GBM patients with worse prognosis, underscoring the potential for CDH3 as both a biomarker for patient stratification and a possible therapeutic target in GBM. SUPPORT/DISCLOSURE Financial support was provided by FCT - Fundação para a Ciência e a Tecnologia - https: //doi.org/10.54499/2022.04859.PTDC, PD/BDE/143154/2019, COVID/BDE/153298/2023, co-funded by MCTES, FSE, UE, and NORTE 2020; and by National funds through FCT - https: //doi.org/10.54499/UIDB/50026/2020, https: //doi.org/10.54499/UIDP/50026/2020, and https: //doi.org/10.54499/LA/P/0050/2020, and by the projects NORTE-01-0145-FEDER-000039, and NORTE-01-0145-FEDER-000055, supported by NORTE 2020, under the PORTUGAL 2020 Partnership Agreement through the European Regional Development Fund (ERDF).
Source: Neuro-Oncology
Authors: E P Martins, C S Gonçalves, J Peixoto, J M Ferreira, S Queirós, A Longatto-Filho, P M Costa, N S Osório, S Granja, B M Costa
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4414799591
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