Senescence, Necrosis, and Apoptosis Govern Circulating Cell-free DNA Release Kinetics

Ariana Rostami; Meghan Lambie; Caberry W Yu; Vuk Stambolic; John N Waldron; Scott V Bratman

doi:10.1016/j.celrep.2020.107830

Senescence, Necrosis, and Apoptosis Govern Circulating Cell-free DNA Release Kinetics

Cell Rep. 2020 Jun 30;31(13):107830. doi: 10.1016/j.celrep.2020.107830.

Authors

Ariana Rostami¹, Meghan Lambie¹, Caberry W Yu², Vuk Stambolic¹, John N Waldron³, Scott V Bratman⁴

Affiliations

¹ Princess Margaret Cancer Center, University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada.
² Princess Margaret Cancer Center, University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada.
³ Princess Margaret Cancer Center, University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Radiation Oncology, University of Toronto, 149 College Street, Toronto, ON M5T 1P5, Canada.
⁴ Princess Margaret Cancer Center, University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Radiation Oncology, University of Toronto, 149 College Street, Toronto, ON M5T 1P5, Canada. Electronic address: scott.bratman@rmp.uhn.ca.

PMID: 32610131
DOI: 10.1016/j.celrep.2020.107830

Abstract

The kinetics of circulating cell-free DNA (cfDNA) release may provide a real-time assessment of induced cell death. However, there is a limited understanding of the underlying biological rationale for cfDNA release following distinct treatments and cell death mechanisms. Here, we uncover a complex interplay between apoptosis, necrosis, and senescence in determining cfDNA release kinetics. Utilizing multiple in vitro and in vivo preclinical models, we show how cfDNA release is modulated through a combination of apoptotic and senescent triggers and inhibitors. Interestingly, we identify treatment-induced senescence as a previously unrecognized determinant of cfDNA kinetics that can counteract its release. Necrosis is the predominant cell death mechanism that consistently contributes to cfDNA release in response to ionizing radiation, and, surprisingly, apoptosis plays a comparatively minor role in some tumors. Based on our results, we propose a model to explain cfDNA release from cells over time, with important implications for future studies.

Keywords: apoptosis; circulating cell-free DNA; kinetics; liquid biopsy; navitoclax; necrosis; radiotherapy; senescence; treatment monitoring.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis*
Cell Line, Tumor
Cell-Free Nucleic Acids / metabolism*
Cellular Senescence*
DNA Damage
Humans
Kinetics
Male
Mice, Inbred NOD
Mice, SCID
Necrosis
Xenograft Model Antitumor Assays

Substances

Cell-Free Nucleic Acids