Mitochondria-associated gene expression perturbation predicts clinical outcomes and shows potential for targeted therapy in neuroblastoma

Abstract

BackgroundMitochondria have long been considered a potential target in cancer therapy because malignant cells are known for their altered energy production. However, there is a lack of comprehensive research on the involvement of mitochondria-associated proteins (MAPs) in neuroblastoma (NB), and their potential as therapeutic targets is yet to be fully explored.MethodsMAP genes were defined based on the protein-coding genes with mitochondrial localization. The mRNA expression patterns and dynamics of MAP genes associated with NB were investigated by integrating publicly available transcriptional profiles at the cellular and tissue levels. Multivariate Cox regression analysis was conducted to reveal the association of MAP genes with the overall survival (OS) and clinical subgroups of NB patients. The single-cell RNA-seq dataset and gene dependency screening datasets were analyzed to reveal the therapeutic potential of targeting MAP genes.ResultsWe compiled a total of 1,712 MAP genes. We found the global and cell type-specific mRNA expression changes of the MAP genes associated with NB status and survival. Our analyses revealed a group of MAP gene signatures independent of MYCN-amplification status associated with NB outcome. We provided computational evidence with selected MAP genes showing good performance in predicting long-term prognosis. By analyzing gene dependency of the MAP genes in NB cell lines and ex vivo human primary T cells, we demonstrated the therapeutic potential of targeting several MAP genes in NB tumors.ConclusionsCollectively, our study provides evidence for the MAP genes as extended candidates in NB tumor stratification and staging, prognostic prediction, and targeted drug development.

A mitochondria-related genes associated neuroblastoma signature - based on bulk and single-cell transcriptome sequencing data analysis, and experimental validation

“…The interaction between tumor cells and the tumor microenvironment (TME) is also modulated by mitochondrial dynamics, which extends to affecting the efficacy of immune cells within the TME, facilitating immune evasion, and contributing to the development of resistance to treatments ( 13 , 14 ). The significance of mitochondria-related genes (MRGs) in malignancies, including but not limited to NB, is evident through their substantial impact on patient prognosis ( 15 – 17 ). Research into MRGs-related prognostic signatures in cancers such as lung adenocarcinoma, stomach adenocarcinoma, and breast cancer has shown promising results ( 18 – 20 ).…”

DataSheet_1.pdf

“…The interaction between tumor cells and the tumor microenvironment (TME) is also modulated by mitochondrial dynamics, which extends to affecting the efficacy of immune cells within the TME, facilitating immune evasion, and contributing to the development of resistance to treatments (13,14). The significance of mitochondria-related genes (MRGs) in malignancies, including but not limited to NB, is evident through their substantial impact on patient prognosis (15)(16)(17). Research into MRGs-related prognostic signatures in cancers such as lung adenocarcinoma, stomach adenocarcinoma, and breast cancer has shown promising results (18)(19)(20).…”