High Cellular Plasticity State of Medulloblastoma: Local Recurrence and Distant Dissemination
High Cellular Plasticity State of Pediatric Medulloblastoma: A Comprehensive Analysis of Local Recurrence and Distant Dissemination
Research Background
Medulloblastoma (MB) is a highly heterogeneous pediatric intracranial malignancy. While current treatments (surgery, radiotherapy, and chemotherapy) improve survival rates after initial treatment, relapse cases generally lack targeted therapies, resulting in limited therapeutic efficacy. Most patients with recurrent MB have a five-year survival rate of less than 10%. Particularly of concern are medulloblastomas with characteristics of local recurrence and distant dissemination, whose unique molecular events and biological properties pose significant challenges to existing treatments.
Recurrent tumors often exhibit treatment resistance, which may be attributed to intratumoral heterogeneity, as well as cellular diversity and genetic instability in their molecular mechanisms. However, the dynamic changes in cellular states during tumor recurrence remain poorly understood. As such, this study aimed to address: How does medulloblastoma evolve highly heterogeneous cell states during recurrence? How do these cellular states drive tumor relapse and dissemination? Can targeting the relevant markers effectively arrest tumor progression?
Source of the Study
The study is published in the January 2025 edition of Cell Reports Medicine, titled “High Cellular Plasticity State of Medulloblastoma Local Recurrence and Distant Dissemination.” This research was spearheaded by Hailong Liu, Jing Zhang, and other collaborators from multiple research and medical institutions, including Beijing Tiantan Hospital and BGI-Shenzhen.
Detailed Description of the Study
a) Study Design and Experimental Workflow
This study combines single-cell and multi-omics analyses to comprehensively characterize the cellular and genetic features of medulloblastoma during recurrence and dissemination. The specific workflow includes the following steps:
Sample Collection and Grouping
A total of 17 medulloblastoma samples were examined, including 9 treatment-naive lesions and 8 recurrent lesions (comprising local recurrences and disseminated lesions). These samples were further classified into the SHH subgroup (Sonic Hedgehog subgroup, SHH-MB, 7 cases) and Group 3 subgroup (G3-MB, 10 cases).Single-Cell Transcriptomics Sequencing
Approximately 150,000 single cells were isolated from the samples, and single-cell RNA sequencing (scRNA-seq) and cell clustering analyses (e.g., Principal Component Analysis - PCA and t-SNE embedding) identified the core cell types within the medulloblastoma ecosystem. Key types include Cycling Tumor Cells, Differentiated Tumor Cells, immune cells (e.g., microglia and T cells), and astrocytes.Single-Cell ATAC Sequencing
To explore how chromatin accessibility (CA) influences gene expression and cellular state transitions, single-nucleus ATAC sequencing (snATAC-seq) was utilized to discern the genetic traits of medulloblastoma.Spatial Transcriptomics Analysis
High-resolution spatial transcriptomics techniques were employed to analyze the spatial localization and distribution of cell functions within samples, tracking evolutionary tumor dynamics during recurrence.Targeted Experiments and Functional Validation
The study assessed whether blocking PTPRZ1 (Protein Tyrosine Phosphatase Receptor Type Z1) could effectively suppress the High Cellular Plasticity (HCP) subpopulation and thereby inhibit tumor recurrence and dissemination.
b) Key Findings and Major Results
Characterization of the Cellular Ecosystem
Local recurrences were enriched in Cycling Tumor Cells, whereas disseminated lesions predominantly featured a higher proportion of Differentiated Tumor Cells. This indicates that local recurrences tend to exhibit stronger proliferative traits, while dissemination is more associated with adaptive differentiation.Chromatin Accessibility and Gene Expression
HCP subpopulations exhibited significantly elevated chromatin openness, and genes associated with key transcription factors (e.g., CENPF and PTPRZ1) were highly expressed. These cells demonstrated superior adaptability, driving heterogeneity and drug resistance.Critical Role of High Cellular Plasticity (HCP) State
The HCP subpopulation in recurrent tumors showed pronounced proliferative capacity and stemness traits. Their high plasticity enabled them to differentiate into multiple lineages under environmental pressures, serving as a critical driver of medulloblastoma progression.Chromosomal Variation Insights
Unique chromosomal gains and losses were identified during recurrence, such as the common 7q gain and 11q loss observed in disseminated Group 3 medulloblastoma samples. These copy number variations (CNVs) were validated via whole-genome sequencing techniques.Therapeutic Efficacy of Targeting
In murine models, inhibitors targeting PTPRZ1 (e.g., NAZ2329) significantly reduced tumor proliferation in both local recurrences and lung metastases, while also prolonging survival in experimental animals.
c) Conclusions
This research systematically unveils the key cellular characteristics and genetic drivers underpinning medulloblastoma recurrence and dissemination. The HCP subpopulation offers critical adaptive and proliferative advantages during tumor progression. Its chromatin accessibility and transcription factor activity present an ideal target for therapeutic intervention.
d) Highlights of the Study
- Breakthrough Discovery: The identification of HCP cells as an independent driver of recurrence and dissemination provides a new perspective for understanding medulloblastoma progression.
- Multi-omics Integration: By integrating scRNA-seq, snATAC-seq, and high-resolution spatial transcriptomics, the study comprehensively analyzes the spatiotemporal evolution of tumor cellular states.
- Clinical Potential: Targeting PTPRZ1 markers significantly suppresses medulloblastoma recurrence and dissemination, offering a clear direction for clinical therapy.
e) Significance of the Study
This work fills critical knowledge gaps on the mechanisms underlying medulloblastoma recurrence and dissemination. It highlights the indispensable role of HCP cells in tumor relapse and provides a solid foundation for developing more effective personalized treatment strategies.