AUTHOR=Wade James D. , Lun Xiao-Kang , Zivanovic Nevena , Voit Eberhard O. , Bodenmiller Bernd 

TITLE=Mechanistic Model of Signaling Dynamics Across an Epithelial Mesenchymal Transition

JOURNAL=Frontiers in Physiology

VOLUME=Volume 11 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2020.579117

DOI=10.3389/fphys.2020.579117

ISSN=1664-042X

ABSTRACT=Intracellular signaling pathways are at the core of cellular information processing. The
states of these pathways and their inputs determine signaling dynamics and drive cell function.
Within a cancerous tumor, many combinations of cell states and microenvironments can lead
to dramatic variations in responses to treatment. Network rewiring has been thought to under-
lie these context-dependent divterences in signaling; however, from a biochemical standpoint,
rewiring of signaling networks should not be a prerequisite for heterogeneity in responses to
stimuli. Here we address this conundrum by analyzing an in vitro model of the epithelial mes-
enchymal transition (EMT), a biological program implicated in increased tumor invasiveness,
heterogeneity, and drug resistance. We used mass cytometry to measure EGF signaling dynam-
ics in the ERK and AKT signaling pathways before and after induction of EMT in Py2T murine
breast cancer cells. Analysis of the data with standard network inference methods suggested
EMT-dependent network rewiring. In contrast, use of a modeling approach that adequately
accounts for single-cell variation demonstrated that a single reaction-based pathway model with
constant structure and near-constant parameters is sucocient to represent divterences in EGF
signaling across EMT. This result indicates that rewiring of the signaling network is not nec-
essary for heterogeneous responses to a signal and that unifying reaction-based models should
be employed for characterization of signaling in heterogeneous environments such as cancer.