PO-105 CDH3/P-cadherin as a novel biomarker in glioblastoma: functional and prognostic insights

Abstract

IntroductionGlioblastoma (GBM) is the most common and malignant primary brain tumour in adults. Patients diagnosed with GBM exhibit a poor prognosis with a median survival of approximately 15 months. P-cadherin (encoded by CDH3) is a classical cadherin that contributes for cell-cell adhesion by homophilic interactions, and is being studied and considered an attractive therapeutic target in several cancer types. Critically, its relevance in GBM is completely unknown. In this study, we investigate the functional roles and prognostic value of P-cadherin in this highly malignant form of gliomas.Material and methodsCDH3 mRNA expression was evaluated in glioma patients available in TCGA database, and at the protein level by immunohistochemistry in our dataset of glioma patients from Hospital Braga. CDH3/P-cadherin functional roles were assessed in vitro using silencing (in two primary GBM cell lines) and overexpression (a commercially available GBM cell line) models. In vitro functional assays included evaluation of cell viability (trypan blue and MTS), migration (wound healing), invasion (Matrigel chamber), and stemness features (neurosphere formation). In vivo, subcutaneous and orthotopic intracranial GBM xenografts were established in Nude and NOD-scid gamma (NSG) mice, respectively. CDH3 expression in GBM samples was evaluated by RT-qPCR and its relevance in patients’ prognosis was evaluated using the Log-rank test.Results and discussionsWe found CDH3 expression is higher in high-grade gliomas. CDH3-silencing and overexpression GBM models show CDH3/P-Cadherin regulates GBM cell viability, invasion, migration and stemness capacity. In vivo CDH3-overexpressing cells generate larger subcutaneous tumours, and when orthotopically injected cause shorter overall survival of mice. Concordantly, higher CDH3 expression is predictive of shorter overall and recurrence-free survivals in various cohorts of GBM patients.ConclusionTogether, our results show for the first time CDH3/P-cadherin is associated with GBM aggressiveness and patient prognosis, suggesting it may be an attractive therapeutic target in this deadly brain tumour.