Stochastic Network Model of Receptor Cross-Talk Predicts Anti-Angiogenic Effects

TL;DR

This paper develops a stochastic Boolean network model of receptor cross-talk in angiogenesis, revealing robust signaling responses and identifying unstable feedback loops that could influence cancer therapy strategies.

Contribution

It is the first to model receptor cross-talk in angiogenesis using a stochastic Boolean network, providing insights into signal stability and cell fate decisions.

Findings

Network exhibits rapid, stable responses to external stimuli.

Oscillatory feedback between RhoA and Rac1 is unstable under noise.

Cell death probability increases with molecular noise.

Abstract

Cancer invasion and metastasis depend on angiogenesis. The cellular processes (growth, migration, and apoptosis) that occur during angiogenesis are tightly regulated by signaling molecules. Thus, understanding how cells synthesize multiple biochemical signals initiated by key external stimuli can lead to the development of novel therapeutic strategies to combat cancer. In the face of large amounts of disjoint experimental data generated from multitudes of laboratories using various assays, theoretical signal transduction models provide a framework to distill this vast amount of data. Such models offer an opportunity to formulate and test new hypotheses, and can be used to make experimentally verifiable predictions. This study is the first to propose a network model that highlights the cross-talk between the key receptors involved in angiogenesis, namely growth factor, integrin, and cadherin receptors. From available experimental data, we construct a stochastic Boolean network model of receptor cross-talk, and systematically analyze the dynamical stability of the network under continuous-time Boolean dynamics with a noisy production function. We find that the signal transduction network exhibits a robust and fast response to external signals, independent of the internal cell state. We derive an input-output table that maps external stimuli to cell phenotypes, which is extraordinarily stable against molecular noise with one important exception: an oscillatory feedback loop between the key signaling molecules RhoA and Rac1 is unstable under arbitrarily low noise, leading to erratic, dysfunctional cell motion. Finally, we show that the network exhibits an apoptotic response rate that increases with noise, suggesting that the probability of programmed cell death depends on cell health.