Pre-existing Cell States Control Heterogeneity of Both EGFR and CXCR4 Signaling.

Abstract

INTRODUCTION:

CXCR4 and epidermal growth factor receptor (EGFR) represent two major families of receptors, G-protein coupled receptors and receptor tyrosine kinases, with central functions in cancer. While utilizing different upstream signaling molecules, both CXCR4 and EGFR activate kinases ERK and Akt, although single-cell activation of these kinases is markedly heterogeneous. One hypothesis regarding the origin of signaling heterogeneity proposes that intercellular variations arise from differences in pre-existing intracellular states set by extrinsic noise. While pre-existing cell states vary among cells, each pre-existing state defines deterministic signaling outputs to downstream effectors. Understanding causes of signaling heterogeneity will inform treatment of cancers with drugs targeting drivers of oncogenic signaling.

METHODS:

We built a single-cell computational model to predict Akt and ERK responses to CXCR4- and EGFR-mediated stimulation. We investigated signaling heterogeneity through these receptors and tested model predictions using quantitative, live-cell time-lapse imaging.

RESULTS:

We show that the pre-existing cell state predicts single-cell signaling through both CXCR4 and EGFR. Computational modeling reveals that the same set of pre-existing cell states explains signaling heterogeneity through both EGFR and CXCR4 at multiple doses of ligands and in two different breast cancer cell lines. The model also predicts how phosphatidylinositol-3-kinase (PI3K) targeted therapies potentiate ERK signaling in certain breast cancer cells and that low level, combined inhibition of MEK and PI3K ablates potentiated ERK signaling.

CONCLUSIONS:

Our data demonstrate that a conserved motif exists for EGFR and CXCR4 signaling and suggest potential clinical utility of the computational model to optimize therapy.

• Authors: Phillip C Spinosa, Patrick C Kinnunen, Brock A Humphries, Gary D Luker, Kathryn E Luker, Jennifer J Linderman
• Journal: Cellular and molecular bioengineering (Cell Mol Bioeng) Vol. 14 Issue 1 Pg. 49-64 (Feb 2021) ISSN: 1865-5025 [Print] United States
• PMID: 33643466 (Publication Type: Journal Article)
• Copyright: © Biomedical Engineering Society 2020.