In vivo cisplatin-resistant neuroblastoma metastatic model reveals tumour necrosis factor receptor superfamily member 4 (TNFRSF4) as an independent prognostic factor of survival in neuroblastoma

PLoS One. 2024 May 29;19(5):e0303643. doi: 10.1371/journal.pone.0303643. eCollection 2024.

Abstract

Neuroblastoma is the most common solid extracranial tumour in children. Despite major advances in available therapies, children with drug-resistant and/or recurrent neuroblastoma have a dismal outlook with 5-year survival rates of less than 20%. Therefore, tackling relapsed tumour biology by developing and characterising clinically relevant models is a priority in finding targetable vulnerability in neuroblastoma. Using matched cisplatin-sensitive KellyLuc and resistant KellyCis83Luc cell lines, we developed a cisplatin-resistant metastatic MYCN-amplified neuroblastoma model. The average number of metastases per mouse was significantly higher in the KellyCis83Luc group than in the KellyLuc group. The vast majority of sites were confirmed as having lymph node metastasis. Their stiffness characteristics of lymph node metastasis values were within the range reported for the patient samples. Targeted transcriptomic profiling of immuno-oncology genes identified tumour necrosis factor receptor superfamily member 4 (TNFRSF4) as a significantly dysregulated MYCN-independent gene. Importantly, differential TNFRSF4 expression was identified in tumour cells rather than lymphocytes. Low TNFRSF4 expression correlated with poor prognostic indicators in neuroblastoma, such as age at diagnosis, stage, and risk stratification and significantly associated with reduced probability of both event-free and overall survival in neuroblastoma. Therefore, TNFRSF4 Low expression is an independent prognostic factor of survival in neuroblastoma.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cisplatin* / pharmacology
  • Cisplatin* / therapeutic use
  • Drug Resistance, Neoplasm* / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lymphatic Metastasis
  • Mice
  • N-Myc Proto-Oncogene Protein / genetics
  • N-Myc Proto-Oncogene Protein / metabolism
  • Neuroblastoma* / drug therapy
  • Neuroblastoma* / genetics
  • Neuroblastoma* / metabolism
  • Neuroblastoma* / mortality
  • Neuroblastoma* / pathology
  • Prognosis

Substances

  • Cisplatin
  • N-Myc Proto-Oncogene Protein
  • MYCN protein, human

Grants and funding

O.P. received support for this project through Neuroblastoma UK, RCSI Strategic Academic Recruitment (StAR) Programme, Health Research Board - The Conor Foley Neuroblastoma Cancer Research Foundation (HRCI-HRB-2022-013). C.G. was funded by Irish Research Council Postgraduate Programme (GOIPG/2019/3220), R.S. - Irish Research Council - The Conor Foley Neuroblastoma Cancer Research Foundation (EPSPG/2021/95). M.S. was funded by Instituto de Salud Carlos III through the projects “ICI21/00076”, “PI23/01144” and “PMP21/00073” (Co-funded by the European Regional Development Fund/European Social Fund; “A way to make Europe”/ “Investing in your future”). L.D.-J. is recipient of a Ramón y Cajal scheme (Grant No. RyC-2021-034346-I), funded by the Spanish Ministry for Science and Innovation (MCIN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.