scCirclehunter delineates ecDNA-containing cells using single-cell ATAC-seq, with a focus on glioblastoma

Area of Science:

• Genomics
• Cancer Biology
• Single-cell analysis

Background:

• Extrachromosomal DNA (ecDNA) is a key driver of tumor heterogeneity and poor prognosis in cancer.
• Limited single-cell resolution studies exist for patient-derived ecDNA.

Purpose of the Study:

• Introduce scCirclehunter, a novel framework to identify ecDNA from single-cell ATAC-seq (scATAC-seq) data.
• Analyze ecDNA heterogeneity and cellular trajectories in glioblastoma (GBM) patients.
• Investigate mechanisms of ecDNA-driven tumor progression and potential links to mitochondrial transfer.

Main Methods:

• Developed scCirclehunter for ecDNA identification and cell population assignment from scATAC-seq data.
• Applied scCirclehunter to glioblastoma datasets.
• Integrated scRNA-seq data for mechanistic insights and analysis of ecNR2E1.
• Examined intercellular heterogeneity and cell trajectories.

Main Results:

• Uncovered significant inter-cellular heterogeneity of ecDNA-carrying cells across GBM patients.
• Traced malignant cell trajectories in patients with multiple ecDNAs.
• Demonstrated ecDNA drives GBM progression via multiple mechanisms, exemplified by ecNR2E1.
• Observed a potential link between ecDNA and increased mitochondrial transfer frequency.

Conclusions:

• scCirclehunter offers a powerful framework for single-cell precision analysis of patient-specific ecDNAs.
• Provides critical insights into the role of ecDNA-carrying cells in driving GBM heterogeneity.
• Highlights ecDNA as a significant factor in glioblastoma pathogenesis and progression.