Towards a predictive and deterministic understanding of transmitotic cell fates during TRAIL-induced cell death signalling

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A subtle balance between cell proliferation and cell death is fundamental for many physiological processes and its dysregulation is implicated in the development of cancer. Programmed cell death, such as apoptosis, can be triggered by ligands that bind to cell-surface death receptors. We recently found that cell cycle progression modulates the susceptibility to TRAIL-induced apoptosis in cancer cells: Interestingly, substantial numbers of cells that progress through mitosis suffer sublethal apoptotic DNA damage and ultimately escape from extrinsic apoptosis. However, the fate (death vs. escape/survival) of individual cells within isogenic populations in this scenario currently cannot be predicted. At the present time, we lack an understanding for how and when cell fates are (pre-)determined following TRAIL treatment in this context. Additionally, we currently do not know quantitatively and kinetically how Mcl-1, the major Bcl-2 family member that confers transmitotic apoptosis resistance, is degraded after normal progression through mitosis to re-establish apoptosis susceptibility. We will approach these important open questions by detailed quantitative and kinetic studies and by systems biological approaches, taking advantage of our innovative tools to monitor cell cycle progression and cell death signalling in parallel. In addition, we will validate to which extent transmitotic resistance to or escape from TRAIL-induced apoptosis can be observed in more complex cell growth scenarios, including experimentally well controllable 3D spheroids and in vivo settings. Extrinsic apoptosis will be triggered by a superior 2nd generation and translationally relevant hexameric TRAIL variant, increasing the application relevance of the research programme. Substantial amounts of highly promising data have been collected that support our research objectives. Overall, we are convinced that the planned work will allow us to transition from description and observation towards a predictive and deterministic understanding of cell fate decision making in the interplay of extrinsically induced cell death signalling and cell cycle progression. Our work addresses a currently largely unstudied but impactful topic that is highly relevant for understanding a crucial facet of cell death-regulation and –escape.