Short-term memory of past caspase activity biases cell elimination in vivo.

Apoptosis is triggered by the activation of Caspases leading to irreversible engagement in cell death. However, recent data outline numerous non-apoptotic functions of caspases as well as quite ubiquitous sublethal activation of effector caspases in vivo, opening the question of what drives the bifurcation between cell death and survival. Using quantitative live imaging combined with machine learning and optogenetics in the Drosophila pupal notum (a single-layer epithelium), we reveal the existence of a large heterogeneity of caspase activity thresholds between cells and distinct spatial domains with low or high sensitivity to caspases. We outline the central role of past exposure to sublethal caspase activity, which sensitises cells to apoptosis for several hours and reduces their threshold, and can bias single-cell elimination. Altogether, this work reveals the role of a cell's past history for apoptosis regulation in vivo, which can bias clonal selection and the spatial pattern of cell death.