Abstract
A large fraction of human cancers contain genetic alterations within the Mitogen Activated Protein Kinase (MAPK) signaling network that promote unpredictable phenotypes. Previous studies have shown that the temporal patterns of MAPK activity (i.e. signaling dynamics) differentially regulate cell behavior. However, the role of signaling dynamics in mediating the effects of cancer driving mutations has not been systematically explored. Here, we show that oncogene expression leads to either pulsatile or sustained ERK activity that correlate with opposing cellular behaviors (i.e. proliferation vs. cell cycle arrest, respectively). Moreover, sustained-but not pulsatile-ERK activity triggers ERK activity waves in unperturbed neighboring cells that depend on the membrane metalloprotease ADAM17 and EGFR activity. Interestingly, the ADAM17-EGFR signaling axis coordinates neighboring cell migration toward oncogenic cells and is required for oncogenic cell extrusion. Overall, our data suggests that the temporal patterns of MAPK activity differentially regulate cell autonomous and non-cell autonomous effects of oncogene expression.
Highlights
The Receptor-Tyrosine Kinase (RTK)/RAS/ERK signaling axis (Figure 1A) is mutated in most human cancers (Sanchez-Vega et al, 2018)
To study the effects of oncogene expression on the temporal patterns of MAPK signaling we generated a reporter cell line derived from the chromosomally-normal human breast epithelial line, MCF10A, expressing the ERK Kinase Translocation Reporter (Regot et al, 2014) (ERK KTR) and a fluorescently tagged ERK kinase (ERK-mRuby2)
While our approach is admittedly different than acquisition of point mutations in vivo, ERK dynamics resulting from oncogene overexpression robustly correlated with the same cellular phenotypes: (i) pulsatile ERK activity correlates with increased proliferation and, (ii) sustained ERK activity leads to cell cycle arrest similar to OIS (Hahn and Weinberg, 2002; Courtois-Cox et al, 2006; Kuilman et al, 2008)
Summary
The Receptor-Tyrosine Kinase (RTK)/RAS/ERK signaling axis (Figure 1A) is mutated in most human cancers (Sanchez-Vega et al, 2018). The mechanisms underlying dose-dependent effects of ERK signaling have been intensely studied using bulk cell population assays. In vivo and in vitro studies have shown that pulsatile or sustained ERK activity have different effects on cell behavior (Albeck et al, 2013; Aoki et al, 2013; de la Cova et al, 2017; Johnson and Toettcher, 2019; Santos et al, 2007; Bugaj et al, 2018; Aoki et al, 2017). Whether different oncogenic perturbations have different functional outcomes depending on downstream signaling dynamics remains unknown. To address this question, an isogenic single-cell approach with temporal control of oncogene expression is needed
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