PT - JOURNAL ARTICLE AU - Reema Baskar AU - Harris G Fienberg AU - Zumana Khair AU - Patricia Favaro AU - Sam Kimmey AU - Douglas R Green AU - Garry P Nolan AU - Sylvia Plevritis AU - Sean C Bendall TI - TRAIL-induced variation of cell signaling states provides nonheritable resistance to apoptosis AID - 10.26508/lsa.201900554 DP - 2019 Dec 01 TA - Life Science Alliance PG - e201900554 VI - 2 IP - 6 4099 - https://www.life-science-alliance.org/content/2/6/e201900554.short 4100 - https://www.life-science-alliance.org/content/2/6/e201900554.full SO - Life Sci. Alliance2019 Dec 01; 2 AB - TNFα-related apoptosis-inducing ligand (TRAIL), specifically initiates programmed cell death, but often fails to eradicate all cells, making it an ineffective therapy for cancer. This fractional killing is linked to cellular variation that bulk assays cannot capture. Here, we quantify the diversity in cellular signaling responses to TRAIL, linking it to apoptotic frequency across numerous cell systems with single-cell mass cytometry (CyTOF). Although all cells respond to TRAIL, a variable fraction persists without apoptotic progression. This cell-specific behavior is nonheritable where both the TRAIL-induced signaling responses and frequency of apoptotic resistance remain unaffected by prior exposure. The diversity of signaling states upon exposure is correlated to TRAIL resistance. Concomitantly, constricting the variation in signaling response with kinase inhibitors proportionally decreases TRAIL resistance. Simultaneously, TRAIL-induced de novo translation in resistant cells, when blocked by cycloheximide, abrogated all TRAIL resistance. This work highlights how cell signaling diversity, and subsequent translation response, relates to nonheritable fractional escape from TRAIL-induced apoptosis. This refined view of TRAIL resistance provides new avenues to study death ligands in general.