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Nuclei Isolation from Fresh Frozen Brain Tumors for Single-Nucleus RNA-seq and ATAC-seq
Published on: August 25, 2020
Inferred developmental origins of brain tumors from single-cell RNA-sequencing data
Su Wang1, Rachel Naomi Curry2,3, Malcolm F McDonald4,5,2
1Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, USA.
Background:
The reactivation of neurodevelopmental programs in cancer highlights parallel biological processes that occur in both normal development and brain tumors. Achieving a deeper understanding of how dysregulated developmental factors play a role in the progression of brain tumors is therefore crucial for identifying potential targets for therapeutic interventions. Single-cell RNA-sequencing (scRNA-Seq) provides an opportunity to understand how developmental programs are dysregulated and reinitiated in brain tumors at single-cell resolution. The aim of this study is to identify the developmental origins of brain tumors using scRNA-Seq data.
Methods:
Here, we introduce COORS (Cell Of ORigin like CellS), a computational tool trained on developmental human brain single-cell datasets that annotates "developmental-like" cell states in brain tumors. COORS leverages cell type-specific multilayer perceptron models and incorporates a developmental cell type tree that reflects hierarchical relationships and models cell type probabilities.
Results:
Applying COORS to various brain cancer datasets, including medulloblastoma (MB), glioma, and diffuse midline glioma (DMG), we identified developmental-like cells that represent putative cells of origin in these tumors. Our method provides both cell of origin classification and cell age regression, offering insights into the developmental cell types of tumor subgroups. COORS identified outer radial glia developmental cells within IDHWT glioma cells whereas oligodendrocyte precursor cells (OPCs) and neuronal-like cells in IDHMut. Interestingly, IDHMut subgroup cells that map to OPC show bimodal distributions that are both early and late weeks in development. Furthermore, COORS offers a valuable resource by providing novel markers linked to developmental states within MB, glioma, and DMG tumor subgroups.
Conclusions:
Our work adds to our cumulative understanding of brain tumor heterogeneity and helps pave the way for tailored treatment strategies.
Insights
A new computational tool, COORS, identifies developmental origins of brain tumors by analyzing single-cell RNA sequencing data. This tool aids in understanding tumor heterogeneity and developing targeted therapies for brain cancers.
Area of Science:
- Neuroscience
- Oncology
- Computational Biology
Background:
- Reactivation of neurodevelopmental programs is observed in cancer, suggesting shared biological processes between development and brain tumors.
- Understanding dysregulated developmental factors in brain tumor progression is crucial for identifying therapeutic targets.
- Single-cell RNA sequencing (scRNA-Seq) enables high-resolution analysis of developmental program dysregulation in brain tumors.
Purpose of the Study:
- To identify the developmental origins of brain tumors using scRNA-Seq data.
- To develop a computational tool for annotating developmental-like cell states in brain tumors.
Main Methods:
- Introduction of COORS (Cell Of ORigin like CellS), a computational tool trained on human brain developmental scRNA-Seq datasets.
- COORS utilizes cell type-specific multilayer perceptron models and a developmental cell type tree to model cell type probabilities.
- Application of COORS to medulloblastoma (MB), glioma, and diffuse midline glioma (DMG) datasets.
Main Results:
- COORS identified developmental-like cells representing putative cells of origin in MB, glioma, and DMG.
- The tool provides cell of origin classification and cell age regression, revealing developmental insights into tumor subgroups.
- Specific findings include identification of outer radial glia in IDHWT glioma and oligodendrocyte precursor cells (OPCs) and neuronal-like cells in IDHMUT glioma, with OPCs showing bimodal developmental timing.
Conclusions:
- The study enhances understanding of brain tumor heterogeneity by pinpointing developmental origins.
- COORS provides novel markers associated with developmental states in brain tumors.
- This research contributes to paving the way for tailored therapeutic strategies in brain oncology.
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