Multi-range ERK responses shape the proliferative trajectory of single cells following oncogene induction

Oncogene-induced senescence is a phenomenon in which aberrant oncogene expression causes non -trans-formed cells to enter a non-proliferative state. Cells undergoing oncogenic induction display phenotypic het-erogeneity, with some cells senescing and others remaining proliferative. The causes of heterogeneity remain unclear. We studied the sources of heterogeneity in the responses of human epithelial cells to oncogenic BRAFV600E expression. We found that a narrow expression range of BRAFV600E generated a wide range of activities of its downstream effector ERK. In population-level and single-cell assays, ERK activity displayed a non-monotonic relationship to proliferation, with intermediate ERK activities leading to maximal proliferation. We profiled gene expression across a range of ERK activities over time and characterized four distinct ERK response classes, which we propose act in concert to generate the ERK-proliferation response. Altogether, our studies map the input-output relationships between ERK activity and proliferation, elucidating how het-erogeneity can be generated during oncogene induction.

Automated summary

Oncogene-induced senescence is a phenomenon where abnormal oncogene expression leads to non-proliferative state in non-transformed cells. The heterogeneity in cellular response during oncogenic induction remains unclear. However, our study on human epithelial cells revealed that a narrow range of BRAFV600E expression resulted in a wide range of downstream ERK activities, which displayed a non-monotonic relationship with proliferation. We identified four distinct ERK response classes that together contribute to ERK-proliferation response and generation of heterogeneity.