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
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.
Funding
Neuroblastoma UK
RCSI Strategic Academic Recruitment (StAR) Programme
Health Research Board - The Conor Foley Neuroblastoma Cancer Research Foundation (HRCI-HRB-2022-013)
Irish Research Council Postgraduate Programme (GOIPG/2019/3220)
Irish Research Council - The Conor Foley Neuroblastoma Cancer Research Foundation (EPSPG/2021/95)
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”)
Ramón y Cajal scheme (Grant No. RyC-2021-034346-I)
Spanish Ministry for Science and Innovation (MCIN)
TITLE: Phase I trial of ABTL0812 in children with relapsed or refractory neuroblastoma and extra-cranial solid tumors
Instituto de Salud Carlos III
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Data Availability Statement
Data is contained within the article or Supporting Information material. RNA sequencing data “NeuroblastomaKellyLuc-Kelly83Luc xenografts, the HTG EdgeSeq immuno-oncology panel” is deposited at R2:Genomics Analysis and Visualization Platform (http://r2.amc.nl; ID: Xenograft Neuroblastoma KellyLuc (Immuno-oncology panel) - Piskareva-10 - custom - rsg001Comments
The original article is available at https://journals.plos.org/Published Citation
Murphy C. et al. 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;19(5):e0303643.Publication Date
29 May 2024External DOI
PubMed ID
38809883Department/Unit
- Amber (Advanced Material & Bioengineering Research) Centre
- Anatomy and Regenerative Medicine
- Data Science Centre
- School of Pharmacy and Biomolecular Sciences
- School of Population Health
- Tissue Engineering Research Group (TERG)
Publisher
Public Library of ScienceVersion
- Published Version (Version of Record)