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Neuroblastoma Cells Depend on CSB for Faithful Execution of Cytokinesis and Survival.

ABSTRACT: Neuroblastoma, the most common extra-cranial solid tumor of early childhood, is one of the major therapeutic challenges in child oncology: it is highly heterogenic at a genetic, biological, and clinical level. The high-risk cases have one of the least favorable outcomes amongst pediatric tumors, and the mortality rate is still high, regardless of the use of intensive multimodality therapies. Here, we observed that neuroblastoma cells display an increased expression of Cockayne Syndrome group B (CSB), a pleiotropic protein involved in multiple functions such as DNA repair, transcription, mitochondrial homeostasis, and cell division, and were recently found to confer cell robustness when they are up-regulated. In this study, we demonstrated that RNAi-mediated suppression of CSB drastically impairs tumorigenicity of neuroblastoma cells by hampering their proliferative, clonogenic, and invasive capabilities. In particular, we observed that CSB ablation induces cytokinesis failure, leading to caspases 9 and 3 activation and, subsequently, to massive apoptotic cell death. Worthy of note, a new frontier in cancer treatment, already proved to be successful, is cytokinesis-failure-induced cell death. In this context, CSB ablation seems to be a new and promising anticancer strategy for neuroblastoma therapy.

SUBMITTER: Paccosi E

PROVIDER: S-EPMC8465547 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Neuroblastoma Cells Depend on CSB for Faithful Execution of Cytokinesis and Survival.

Paccosi Elena E Costantino Michele M Balzerano Alessio A Filippi Silvia S Brancorsini Stefano S Proietti-De-Santis Luca L

International journal of molecular sciences 20210917 18

Neuroblastoma, the most common extra-cranial solid tumor of early childhood, is one of the major therapeutic challenges in child oncology: it is highly heterogenic at a genetic, biological, and clinical level. The high-risk cases have one of the least favorable outcomes amongst pediatric tumors, and the mortality rate is still high, regardless of the use of intensive multimodality therapies. Here, we observed that neuroblastoma cells display an increased expression of Cockayne Syndrome group B ( ...[more]

PMID: 34576232

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Project description:To identify mutations that cause defects in mitosis, a collection of mutants in Saccharomyces cerevisiae was screened by a rapid visual assay for abnormal chromosome segregation. From this screen we identified one mutation, pds1-1 that was independently identified in an alternative screen for mutants that exhibit inviability after transient exposure to nocodazole and precocious disassociation of sister chromatids (Guacci, V., A. Yamamoto, A. Strunnikov, J. Kingsbury, E. Hogan, P. Meluh, and D. Koshland. 1993. CSH Symp. Quant. Biol. 58:677-685; Yamamoto, T.J., G. Li, B. Schaar, I. Szilak, and D.W. Cleveland. 1992. Nature (Lond.). 359:536-539). At 23 degrees C pds1-1 mutants exhibit frequent cell death and a 300-fold increase in chromosome loss compared to wild type. At 37 degrees C pds1-1 cells fail to elongate their spindles during anaphase. This spindle defect of pds1 mutants results from a temperature-sensitive step that occurs around the G1/S boundary about the time of spindle assembly. In the absence of spindle elongation pds1 mutants undergo cytokinesis, leading to the missegregation of both chromosomes and spindle pole bodies. After abnormal cell division pds1-1 mutants also initiate new rounds of DNA replication, spindle pole body duplication, and bud formation. Thus, in the pds1-1 mutant at 37 degrees C, cell cycle progression is uncoupled from the completion of anaphase. A pds1 deletion allele has similar phenotypes to the original allele. Taken together these results suggest that Pds1 protein plays an important role in chromosome segregation at 23 degrees C and an essential role for this process at 37 degrees C. The PDS1 gene encodes a novel 42-kD nuclear protein that has both basic and acidic domains. The level of PDS1 mRNA varies with the cell cycle with maximal accumulation around the G1/S boundary. The stability of Pds1 protein also appears to change during the cell cycle as overproduced Pds1p is stable in S and M but degraded in early G1. Therefore, expression of Pds1p is regulated apparently both transcriptionally and postranslationally during the cell cycle. The phenotypes of pds1 mutants and expression pattern of Pds1p are discussed in the context of other spindle-defective mutants and the knowledge that Pds1 protein is an inhibitor of anaphase (Yamamoto, T.J., G. Li, B. Schaar, I. Szilak, and D.W. Cleveland. 1992. Nature (Lond.). 359:536-539).

Project description:BackgroundNeuroblastoma (NB) represents the most frequent and aggressive form of extracranial solid tumor of infants. Although the overall survival of patients with NB has improved in the last years, more than 50% of high-risk patients still undergo a relapse. Thus, in the era of precision/personalized medicine, the need for high-risk NB patient-specific therapies is urgent.MethodsWithin the PeRsonalizEd Medicine (PREME) program, patient-derived NB tumors and bone marrow (BM)-infiltrating NB cells, derived from either iliac crests or tumor bone lesions, underwent to histological and to flow cytometry immunophenotyping, respectively. BM samples containing a NB cells infiltration from 1 to 50 percent, underwent to a subsequent NB cells enrichment using immune-magnetic manipulation. Then, NB samples were used for the identification of actionable targets and for the generation of 3D/tumor-spheres and Patient-Derived Xenografts (PDX) and Cell PDX (CPDX) preclinical models.ResultsEighty-four percent of NB-patients showed potentially therapeutically targetable somatic alterations (including point mutations, copy number variations and mRNA over-expression). Sixty-six percent of samples showed alterations, graded as "very high priority", that are validated to be directly targetable by an approved drug or an investigational agent. A molecular targeted therapy was applied for four patients, while a genetic counseling was suggested to two patients having one pathogenic germline variant in known cancer predisposition genes. Out of eleven samples implanted in mice, five gave rise to (C)PDX, all preserved in a local PDX Bio-bank. Interestingly, comparing all molecular alterations and histological and immunophenotypic features among the original patient's tumors and PDX/CPDX up to second generation, a high grade of similarity was observed. Notably, also 3D models conserved immunophenotypic features and molecular alterations of the original tumors.ConclusionsPREME confirms the possibility of identifying targetable genomic alterations in NB, indeed, a molecular targeted therapy was applied to four NB patients. PREME paves the way to the creation of clinically relevant repositories of faithful patient-derived (C)PDX and 3D models, on which testing precision, NB standard-of-care and experimental medicines.

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Neuroblastoma Cells Depend on CSB for Faithful Execution of Cytokinesis and Survival.

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Neuroblastoma Cells Depend on CSB for Faithful Execution of Cytokinesis and Survival.

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