Related Experiment Video
Updated: May 21, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Transcriptionally distinct malignant neuroblastoma populations show selective response to adavosertib treatment
Chiao-Hui Hsieh1, Yi-Xuan Chen1, Tzu-Yang Tseng1
1Department of Life Science, National Taiwan University, Taipei, Taiwan.
Abstract:
Neuroblastoma is an aggressive childhood cancer that arises from the sympathetic nervous system. Despite advances in treatment, high-risk neuroblastoma remains difficult to manage due to its heterogeneous nature and frequent development of drug resistance. Drug repurposing guided by single-cell analysis presents a promising strategy for identifying new therapeutic options. Here, we aim to characterize high-risk neuroblastoma subpopulations and identify effective repurposed drugs for targeted treatment. We performed single-cell transcriptomic analysis of neuroblastoma samples, integrating bulk RNA-seq data deconvolution with clinical outcomes to define distinct malignant cell states. Using a systematic drug repurposing pipeline, we identified and validated potential therapeutic agents targeting specific high-risk neuroblastoma subpopulations. Single-cell analysis revealed 17 transcriptionally distinct neuroblastoma subpopulations. Survival analysis identified a highly aggressive subpopulation characterized by elevated UBE2C/PTTG1 expression and poor patient outcomes, distinct from a less aggressive subpopulation with favorable prognosis. Drug repurposing screening identified Adavosertib as particularly effective against the aggressive subpopulation, validated using SK-N-DZ cells as a representative model. Mechanistically, Adavosertib suppressed cell proliferation through AKT/mTOR pathway disruption, induced G2/M phase cell cycle arrest, and promoted apoptosis. Further analysis revealed UBE2C and PTTG1 as key molecular drivers of drug resistance, where their overexpression enhanced proliferation, Adavosertib resistance, and cell migration. This study establishes a single-cell-based drug repurposing strategy for high-risk neuroblastoma treatment. Our approach successfully identified Adavosertib as a promising repurposed therapeutic agent for targeting specific high-risk neuroblastoma subpopulations, providing a framework for developing more effective personalized treatment strategies.
Insights
This study used single-cell analysis to identify aggressive neuroblastoma (NB) subpopulations and found Adavosertib effective against them. This drug repurposing approach offers new hope for treating high-risk NB by targeting specific cancer cell states.
Area of Science:
- Pediatric Oncology
- Cancer Genomics
- Pharmacology
Background:
- Neuroblastoma (NB) is an aggressive childhood cancer with poor outcomes for high-risk cases.
- Drug resistance and tumor heterogeneity complicate current NB treatments.
- Single-cell analysis offers a powerful approach to dissect tumor complexity and identify therapeutic vulnerabilities.
Purpose of the Study:
- To characterize high-risk neuroblastoma subpopulations using single-cell transcriptomics.
- To identify and validate repurposed drugs effective against specific aggressive NB subpopulations.
- To elucidate the molecular mechanisms underlying drug resistance in NB.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) of neuroblastoma samples.
- Integration of scRNA-seq with bulk RNA-seq and clinical data for subpopulation identification.
- Systematic drug repurposing screening and in vitro validation using cell models.
Main Results:
- Identified 17 distinct neuroblastoma subpopulations, including a highly aggressive one with poor prognosis.
- Adavosertib demonstrated significant efficacy against the aggressive subpopulation by disrupting the AKT/mTOR pathway.
- Overexpression of UBE2C/PTTG1 was linked to increased proliferation, drug resistance, and migration in NB cells.
Conclusions:
- Single-cell based drug repurposing is a viable strategy for high-risk neuroblastoma.
- Adavosertib is a promising repurposed drug for targeting specific aggressive NB subpopulations.
- Understanding molecular drivers like UBE2C/PTTG1 can inform personalized treatment strategies for neuroblastoma.
