A computational approach to unraveling TLR signaling in murine mammary carcinoma
Authored by Chun Wai Liew, Tiffany Phuong, Carli B Jones, Samantha Evans, Justin Hoot, Kendall Weedling, Damarcus Ingram, Stacy Nganga, Robert A Kurt
Date Published: 2018
DOI: 10.1016/j.compbiomed.2017.12.013
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Abstract
We developed an agent-based model to simulate a signaling cascade which
allowed us to focus on the behavior of each class of agents
independently of the other classes except when they were in physical
contact. A critical piece was the ratio of the populations of agents
that interact with one another, not their absolute values. This ratio
reflects the effects of the density of each agent in the biological
cascade as well as their size and velocity. Although the system can be
used for any signaling cascade in any cell type, to validate the system
we modeled Toll-like receptor (TLR) signaling in two very different
types of cells; tumor cells and white blood cells. The iterative process
of using experimental data to improve a computational model, and using
predictions from the model to design additional experiments strengthened
our understanding of how TLR signaling differs between normal white
blood cells and tumor cells. The model and experimental data showed that
some of the differences between the tumor cells and normal white blood
cells were related to NF kappa B and TAB3 levels, and also suggested
that tumor cells lacked IRAKM-dependent feedback inhibition as a
negative regulator of TLR signaling. Finally, we found that these
different cell types had distinctly different responses when exposed to
two signals indicating that a more biologically relevant model and
experimental system should address activation of multiple interconnected
signaling cascades, the complexity of which further reinforces the need
for a combined computational and molecular approach.
Tags
Simulation
inflammation
Microenvironment
breast cancer
progression
Expression
Responses
Breast-cancer
Pathways
Computer modeling
Tlr
Tab3
Nf kappa b
Irakm
Factor-kappa-b
Chemoattractant protein-1