Systems analysis of cancer reversion based on a Boolean network model.

Abstract

Cancer reversion, inducing cancer cells into re-differentiated normal cells, has been getting a renewed interest as a new way of cancer therapy to overcome the current limitation of apoptosis-inducing treatment, such as unwanted cell death of normal cells, drug resistance acquisition and drug-induced malignancy. Although there have been some experimental observations on cancer reversion in vitro as well as in vivo since 1907, the underlying mechanism is still largely unknown. In addition, identification of robust therapeutic targets for cancer reversion remains as a great challenge. To investigate the hidden mechanism of cancer reversion and identify promising targets, we have constructed a Boolean network model of the intracellular molecular regulatory network of colon cancer by parsing information from KEGG pathway, PPI networks and various experimental literatures. We have developed a scoring system that can quantitatively measure the cancerous state with eight marker molecules based on network-based stratification. We have validated the network model using stochastic simulation and comparing the results with previous experimental observations. Then we further carried out perturbation analysis of all molecular states in the network to find out therapeutic targets for the reversion of colon cancer. We could successfully validate our network model by reproducing previous experimental results on malignancy regression and re-differentiation by APC restoration of colon cancer cells. Moreover, from one-node perturbation analysis, Akt, NF-κB, β-catenin and GSK3β were suggested as inhibitory targets for cancer reversion while BAX, ATM, MEK were suggested as activation targets for cancer reversion. Furthermore, from multiple node perturbation analysis, a sub-network including APC, β-catenin, c-Myc and Akt was suggested as a key kernel of the cancer reversion mechanism. We found that the primary mechanism of cancer reversion induced by APC restoration is the functional recovery of β-catenin mediated gene expression regulation. We have also proposed various drug targets that can potentially lead to cancer reversion.

Acknowledgements: This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea Government, the Ministry of Science, ICT & Future Planning (2015M3A9A7067220, 2014R1A2A1A10052404, and 2013M3A9A7046303).