Integrated Systems and Technologies : Mathematical Oncology Network Modeling of TGF b Signaling in Hepatocellular Carcinoma Epithelial-to-Mesenchymal Transition Reveals Joint Sonic Hedgehog and Wnt Pathway Activation

Epithelial-to-mesenchymal transition (EMT) is a developmental process hijacked by cancer cells to leave the primary tumor site, invade surrounding tissue, and establish distant metastases. A hallmark of EMT is the loss of E-cadherin expression, and onemajor signal for the induction of EMT is TGFb, which is dysregulated in up to 40% of hepatocellular carcinoma (HCC). We have constructed an EMT network of 70 nodes and 135 edges by integrating the signaling pathways involved in developmental EMT and known dysregulations in invasive HCC. We then used discrete dynamic modeling to understand the dynamics of the EMT network driven by TGFb. Our network model recapitulates known dysregulations during the induction of EMT and predicts the activation of the Wnt and Sonic hedgehog (SHH) signaling pathways during this process. We show, across multiple murine (P2E and P2M) and human HCC cell lines (Huh7, PLC/PRF/5, HLE, and HLF), that the TGFb signaling axis is a conserved driver of mesenchymal phenotype HCC and confirm that Wnt and SHH signaling are induced in these cell lines. Furthermore, we identify by network analysis eight regulatory feedback motifs that stabilize the EMT process and show that thesemotifs involve cross-talk amongmultiplemajor pathways. Ourmodelwill be useful in identifying potential therapeutic targets for the suppression of EMT, invasion, andmetastasis inHCC. Cancer Res; 74(21); 5963–77. 2014 AACR.