Systems-level properties of EGFR/Ras/ERK signalling amplify local signals to generate gene expressionplasticity

Abstract

The EGFR/Ras/ERK signalling pathway is a driver of cancer cell proliferation and metastasis in tumours that exhibit high cell-to-cell heterogeneity. While the signalling activity of this pathway is frequently amplified in tumours, it is not understood how the kinetic aspects of its activation in tumours differ from normal cellular signalling. Using live-cell reporters of ERK signalling in the breast cancer progression series HMT-3522, we found that ERK activity in invasive cells is similar in amplitude to isogenic non-malignant cells but is highly dynamic and more disordered, leading to more heterogeneous expression of ERK target genes. Our analysis reveals that this diversification arises from systems-level functions of the pathway, including intracellular amplification of amphiregulin-mediated paracrine signalling and differential kinetic filtering by genes including Fra-1, c-Myc, and Egr1. Our findings establish a mechanism for the generation of non-genetic tumour cell plasticity arising from the specific quantitative properties of a signal transduction pathway.