Towards a predictive and deterministic understanding of transmitotic cell fates during TRAIL-induced cell death signalling
Final Report Abstract
A subtle balance between cell proliferation and cell death is essential for physiological homeostasis, and its dysregulation contributes to cancer development. In our work, we focused on TRAIL-induced apoptosis, a form of programmed cell death initiated by death receptor signaling, and investigated how cell cycle progression influences cellular susceptibility. Our analyses provided new insights into how and when individual cell fates, death versus survival, are determined following TRAIL stimulation. We elucidated that the anti-apoptotic Bcl-2 family protein MCL-1 plays a central role. Using advanced live-cell imaging, singlecell analysis tools and mathematical modelling, we quantitatively and kinetically characterized MCL-1 dynamics and correlated these with apoptosis susceptibility. Importantly we found that after caspase-8 activation, the cell cycle-regulated amounts of MCL-1 and independently also the regulated redistribution of MCL-1 towards mitochondria sets an overall cell death threshold, individually for every single cell. Altogether, our work has therefore allowed us to obtain a deep understanding of cell fate decisions at the interface of cell cycle progression and extrinsic apoptosis. We addressed a previously understudied but highly relevant facet of cell death regulation, with implications for understanding therapy resistance and improving the efficacy of apoptosis-based cancer therapies.
Publications
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Cell cycle progression and transmitotic apoptosis resistance promote escape from extrinsic apoptosis. Journal of Cell Science, 134(24).
Pollak, Nadine; Lindner, Aline; Imig, Dirke; Kuritz, Karsten; Fritze, Jacques S.; Decker, Lorena; Heinrich, Isabel; Stadager, Jannis; Eisler, Stephan; Stöhr, Daniela; Allgöwer, Frank; Scheurich, Peter & Rehm, Markus
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Low-Level Endothelial TRAIL-Receptor Expression Obstructs the CNS-Delivery of Angiopep-2 Functionalised TRAIL-Receptor Agonists for the Treatment of Glioblastoma. Molecules, 26(24), 7582.
Krishna Moorthy, Nivetha; Seifert, Oliver; Eisler, Stephan; Weirich, Sara; Kontermann, Roland E.; Rehm, Markus & Fullstone, Gavin
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Proteasome inhibition triggers the formation of TRAIL receptor 2 platforms for caspase-8 activation that accumulate in the cytosol. Cell Death & Differentiation, 29(1), 147-155.
Hellwig, Christian T.; Delgado, M. Eugenia; Skoko, Josip; Dyck, Lydia; Hanna, Carol; Wentges, Alexa; Langlais, Claudia; Hagenlocher, Cathrin; Mack, Alexandra; Dinsdale, David; Cain, Kelvin; MacFarlane, Marion & Rehm, Markus
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cFLIP downregulation is an early event required for endoplasmic reticulum stress-induced apoptosis in tumor cells. Cell Death & Disease, 13(2).
Mora-Molina, Rocío; Stöhr, Daniela; Rehm, Markus & López-Rivas, Abelardo
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ER stress-induced cell death proceeds independently of the TRAIL-R2 signaling axis in pancreatic β cells. Cell Death Discovery, 8(1).
Hagenlocher, Cathrin; Siebert, Robin; Taschke, Bruno; Wieske, Senait; Hausser, Angelika & Rehm, Markus
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Glioblastoma, from disease understanding towards optimal cell-based in vitro models. Cellular Oncology, 45(4), 527-541.
Boccellato, Chiara & Rehm, Markus
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Mitochondrial genome variations, mitochondrial‐nuclear compatibility, and their association with metabolic diseases. Obesity, 30(6), 1156-1169.
Ludwig‐Słomczyńska, Agnieszka H. & Rehm, Markus
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Interplay of ferroptotic and apoptotic cell death and its modulation by BH3-mimetics. openRxiv.
Qiu, Yun; Hüther, Juliana A.; Wank, Bianca; Rath, Antonia; Tykwe, René; Laschat, Sabine; Conrad, Marcus; Stöhr, Daniela & Rehm, Markus
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TRAIL-induced apoptosis and proteasomal activity – Mechanisms, signalling and interplay. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1871(4), 119688.
Boccellato, Chiara & Rehm, Markus
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Why Bax detection in >1400 publications might be flawed. Cell Death & Disease, 15(12).
Entrop, Kristin; Wieske, Senait & Rehm, Markus
