Gossiping about death: Apoptosis-induced ERK waves as coordinators of multicellular fate decisions

Apoptosis is now recognized as a highly dynamic process that involves the release of a large set of signaling molecules that convey information to cells neighboring an apoptotic site. Recent studies in epithelial systems have discovered that apoptotic cells trigger waves of pulses of mitogen-activated protein kinase (MAPK) / extracellular signal-regulated kinase (ERK) pathway activity in their neighbors. At the single-cell level, the ERK pulses emerge from the MAPK pathway's excitable network properties, such as ultrasensitivity and adaptation. At the cell population level, apoptosis-induced ERK waves (AiEWs) emerge from propagation of ERK pulses across cells via a mechanism that involves mechanical inputs and paracrine signaling. AiEWs enable cell populations to dynamically coordinate fate decision signaling during tissue homeostasis and development. This spatio-temporal signaling mechanism can be hijacked by cancer cells to induce drug-tolerant persister states when apoptosis is triggered by cytotoxic or targeted therapies, undermining treatment efficacy. In this review, we summarize our current understanding of AiEWs, including their initiation, propagation, and coordination of fate decision signaling within a population. We discuss how the relatively simple properties of single cells, and their interactions within a collective coordinate these dynamic signaling patterns. We highlight their implication in resistance to cancer therapy and explore potential strategies to target these waves to re-sensitize cancer cells. Finally, we discuss emerging technologies and future directions to expand the study of this biological phenomenon.