ICAM-2 confers a non-metastatic phenotype in neuroblastoma cells by interaction with α-actinin

• Published in: Oncogene 2015-03, Vol.34 (12), p.1553-1562
• Main Authors: Feduska, J M, Aller, S G, Garcia, P L, Cramer, S L, Council, L N, van Waardenburg, R C A M, Yoon, K J
• Format: Article
• Language: English
• Subjects: 631/67/1922; 631/67/581; 631/80/79; 692/699/67/322; Actinin; Actins - metabolism; Animals; Antigens, CD - chemistry; Antigens, CD - genetics; Antigens, CD - metabolism; Apoptosis; Binding Sites; Cell Adhesion; Cell adhesion & migration; Cell Adhesion Molecules - chemistry; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Cell Biology; Cell Line, Tumor; Cell migration; Cytoskeleton; Female; Genotype & phenotype; Human Genetics; Humans; Internal Medicine; Medicine; Medicine & Public Health; Metastases; Metastasis; Mice; Mice, SCID; Models, Molecular; Mutation; Neoplasm Metastasis; Neuroblastoma; Neuroblastoma - metabolism; Neuroblastoma - pathology; Neuroblastoma cells; Oncology; original-article; Phenotypes; Protein Binding; Proteins; Solid tumors; Tumor cells; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.87

Progressive metastatic disease is a major cause of mortality for patients diagnosed with multiple types of solid tumors. One of the long-term goals of our laboratory is to identify molecular interactions that regulate metastasis, as a basis for developing agents that inhibit this process. Toward this goal, we recently demonstrated that intercellular adhesion molecule-2 (ICAM-2) converted neuroblastoma (NB) cells from a metastatic to a non-metastatic phenotype, a previously unknown function for ICAM-2. Interestingly, ICAM-2 suppressed metastatic but not tumorigenic potential in preclinical models, supporting a novel mechanism of regulating metastasis. We hypothesized that the effects of ICAM-2 on NB cell phenotype depend on the interaction of ICAM-2 with the cytoskeletal linker protein α-actinin. The goal of the study presented here was to evaluate the impact of α-actinin binding to ICAM-2 on the phenotype of NB tumor cells. We used in silico approaches to examine the likelihood that the cytoplasmic domain of ICAM-2 binds directly to α-actinin. We then expressed variants of ICAM-2 with mutated α-actinin-binding domains, and compared the impact of ICAM-2 and each variant on NB cell adhesion, migration, anchorage-independent growth, co-precipitation with α-actinin and production of localized and disseminated tumors in vivo . The in vitro and in vivo characteristics of cells expressing ICAM-2 variants with modified α-actinin-binding domains differed from cells expressing ICAM-2 wild type (WT) and also from cells that expressed no detectable ICAM-2. Like the WT protein, ICAM-2 variants inhibited cell adhesion, migration and colony growth in vitro. However, unlike the WT protein, ICAM-2 variants did not completely suppress development of disseminated NB tumors in vivo . The data suggest the presence of α-actinin-dependent and α-actinin-independent mechanisms, and indicate that the interaction of ICAM-2 with α-actinin is critical to conferring an ICAM-2-mediated non-metastatic phenotype in NB cells.