4.7 Article

Cell-free DNA topology depends on its subcellular and cellular origins in cancer

Journal

JCI INSIGHT
Volume 7, Issue 20, Pages -

Publisher

AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.159590

Keywords

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Funding

  1. Frederick Banting and Charles Best Canada Graduate Scholarship
  2. Canadian Institutes for Health Research
  3. Govern- ment of Ontario
  4. Temerty Faculty of Medicine, University of Toronto
  5. Gattuso-Slaight Personalized Cancer Medicine Fund at the PMCC
  6. Mariano Elia Chair in Head & Neck Cancer Research at University Health Network
  7. University of Toronto
  8. PMCC Head & Neck Translational Program
  9. Wharton Family
  10. Reed Fund
  11. [FBD- 175873]

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Cancer cells release cfDNA, which is predominantly associated with nucleosomal particles and not EVs. Additionally, a subset of mitochondrial cfDNA is membrane protected and derived from non-tumor cells. These findings have important implications for understanding the topology of cfDNA in cancer.
Cancer cells release large quantities of cell-free DNA (cfDNA) into the surrounding tissue and circulation. As cfDNA is a common source of biomarkers for liquid biopsy and has been implicated as a functional mediator for intercellular communication, fundamental characterization of cfDNA topology has widespread biological and clinical ramifications. Whether the topology of cfDNA is such that it exists predominantly in membrane-bound extracellular vesicles (EVs) or in nonvesicular DNA-protein complexes remains poorly understood. Here, we employed a DNA-targeted approach to comprehensively assess total cfDNA topology in cancer. Using preclinical models and patient samples, we demonstrate that nuclear cfDNA is predominantly associated with nucleosomal particles and not EVs, while a substantial subset of mitochondrial cfDNA is membrane protected and disproportionately derived from nontumor cells. In addition, discrimination between membrane-protected and accessible mitochondrial cfDNA added diagnostic and prognostic value in a cohort of head and neck cancer patients. Our results support a revised model for cfDNA topology in cancer. Due to its abundance, nuclear cfDNA within nucleosomal particles is the most compelling liquid biopsy substrate, while EV-bound and accessible mitochondrial cfDNA represent distinct reservoirs of potential cancer biomarkers whose structural conformations may also influence their extracellular stability and propensity for uptake by recipient cells.

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