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
Affiliations
Ariana Rostami
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
Meghan Lambie
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
Caberry W. Yu
Princess Margaret Cancer Center, University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada
Vuk Stambolic
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
John N. Waldron
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
Scott V. Bratman
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; Corresponding author
Summary: 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.
