Abstract 4145: Characterization of the ODZ receptor family in neuroblastoma

Abstract

Abstract Neuroblastoma is the most common extracranial solid tumor of childhood, causing 6% of all childhood cancers but 9% of deaths from malignant tumors in children. It is a tumor with highly heterogeneous clinical behavior, believed to originate from undifferentiated neural crest cells that form the sympathetic nervous system. Neuritogenesis is the process during embryonic development when neural crest cells migrate and differentiate into multiple cell types. The Rho/Rac signaling cascade is fundamental for this process. We performed whole genome sequencing of 40 neuroblastoma tumor samples, 32.5% of the samples contained a mutation in a gene associated with Rho/Rac signaling. The most frequently mutated receptor family among the Rho/Rac associated genes was the tenuerins (ODZ1-4). The ODZ genes were mutated in three out of 40 patients, i.e. 7.5%. The ODZ proteins are not fully characterized, however it is known they are highly expressed during the development of the central nervous system and play role in differentiation of the drosophila fly. Evidence suggests a function for dysregulated expression of the ODZs in human tumors, but investigations of a deeper cellular and molecular understanding in neuroblastoma are missing. The aim of this study is to investigate the ODZ receptors to determine the role and function of these proteins in neuroblastoma tumor development, progression and metastasis. When investigated in publically available and validated neuroblastoma cohorts, low expression levels of ODZ1, ODZ2 and ODZ3 were associated with poor overall survival, while low ODZ4 expression correlated with high overall survival. Our data demonstrated that the ODZ receptors were differently expressed in neuroblastoma cell lines. Preliminary results also showed that siRNA knockdown of ODZ4 in a neuroblastoma cell line led to a 50% decrease in cell viability compared to control, together with morphological changes such as more neurite extensions, suggesting that an inhibition of ODZ4 may result in differentiation. Knockout of the four different ODZ transcripts also showed that the ODZ receptors might have compensatory mechanisms for each other. Our data suggest that activity of the ODZ receptors may be important for neuroblastoma development and that manipulation could offer a possible therapy for neuroblastoma. Citation Format: Teodora Andonova, Per Kogner, John Inge Johnsen, Malin Wickström. Characterization of the ODZ receptor family in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4145.