ADAM23-DEPENDENT INVASIVENESS IN ASTROCYTOMAS IS MEDIATED BY THE EXPRESSION OF EMBRYONIC STEM CELL-RELATED GENES

Background and Aim: Glioblastoma is the most common and lethal primary malignant tumor of central nervous system (CNS), with patients median survival of 15 months highlighting its sharp aggressiveness. These tumors are characterized by a high infiltration rate into brain parenchyma. ADAM23 is a non-catalytic Adam (a disintegrin and metaloprotease) family member that is mostly expressed in the CNS with an important role in controlling neuronal development and differentiation. Due to the role of ADAM23 controlling tumor invasiveness, we aimed to investigate ADAM23 function in malignant astrocytoma mobility phenotypes and its subjacent molecular mechanisms. Methods: Using loss-of-function experiments (shRNA) we evaluate ADAM23 role in migratory/invasive phenotypes in astrocytoma cell lines (U87MG and GSC23). ADAM23 levels were correlated with the survival of nude-mice (orthotopic xenograft model), and patients with astrocytomas (TCGA and CCGA – Gliovis platform). RNA sequencing were used to determine signaling pathways (Gene Set Enrichment Analysis GSEA) controlled by ADAM23. Immunohistochemistry, immunocytochemistry, Western Blot, RT-qPCR, and astrocytoma patients public data were used to investigate the molecular mechanisms underlying the functions of ADAM23. Results: ADAM23-silencing increased migration/invasion capacity of U87MG and GSC23 cells. Complementarily, RNA sequencing data showed a highly enriched gene signature associated with glioblastoma invasion in ADAM23-silenced cell variants. Moreover, ADAM23 higher levels are correlated with worse survival in nudemice and patients with astrocytomas. Searching for the molecular mechanisms whereby ADAM23 regulates astrocytoma infiltration, we found that ADAM23-silenced cells increased the expression of genes committed with embryonic stem cell desdifferentiation. Accordingly, we observed that ADAM23-silenced cells augmented the expression of stemness markers such as OCT4, CYR61, Musashi1, Olig2, Nestin and Sox2. Finally, when we segregate TCGA grade II-III astrocytomas patients with ADAM23 and SOX2 distinct levels, we observed that ADAM23lowSOX2high expression patients presented the highest overall survival in comparison with the other combinations of ADAM23 and SOX2 expressions. Conclusions: Here we identified that ADAM23 controls the invasion of astrocytoma cells. Underlying this phenotype, we observed that ADAM23-silenced cells transcriptionally expressed embryonic stem cell-related genes.