Sample-based modeling reveals bidirectional interplay between cell cycle progression and extrinsic apoptosis

Dirke Imig, Nadine Pollak, Frank Allgöwer, Markus Rehm

Abstract: Author summary TRAIL (TNF-related apoptosis-inducing ligand) induces cell death preferentially in cancer cells. Whether cell cycle progression notably affects extrinsic apoptosis has remained unclear, since systematic experimental and mathematical studies to quantitatively understand such interdependencies remained challenging. Here, we applied statistical and mechanistic modeling, linked with experimental analyses, to determine if cell cycle and apoptosis progression are interconnected. Using sample-based modeling, we demonstrate that times required to commit apoptotic cell death depend on the cell cycle position at the time of TRAIL exposure, with delays manifesting during S phase, around a time that can be defined as a point of apoptosis deceleration (PAD). Overall, cells receiving TRAIL in the G1 phase were more likely to die, providing scope to optimize TRAIL-based treatment strategies with respect to cell cycle dynamics.