MAPK Activity Dynamics Regulate Non-Cell Autonomous Effects of Oncogene Expression

Deregulation of Receptor Tyrosine Kinase (RTK) signaling underlies a large fraction of human cancers. These genetic perturbations lead to a variety of cell autonomous and non-cell autonomous effects ranging from cell proliferation to epithelial cell extrusion (e.g. Epithelial Defense Against Cancer, EDAC). Previous studies have shown that the temporal patterns of RTK-MAPK signaling (i.e. dynamics) can differentially regulate cell physiology. However, the role of signaling dynamics in mediating the effects of cancer driving mutations has not been systematically explored. Using live-cell imaging of signaling biosensors upon induction of oncogenic perturbations, we demonstrate that MAPK activity dynamics are decoded by the ADAM17-EGFR paracrine signaling axis to influence neighboring cell behaviors in epithelial monolayers. Specifically, sustained––but not pulsatile––ERK activity triggers amphiregulin (AREG) release and EGFR-ERK signaling in neighboring cells that coordinates migration and proliferation of neighboring cells to promote oncogenic cell extrusion. Interestingly, both oncogenic and neighboring cells require ERK signaling but with qualitatively different dynamics. Overall, we show that the temporal patterns of MAPK activity differentially regulate cell autonomous and non-cell autonomous effects of oncogene expression.