title: Network modeling of TGFβ signaling in hepatocellular carcinoma epithelial-to-mesenchymal transition reveals joint sonic hedgehog and Wnt pathway activation.
abstract: 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 one major signal for the induction of EMT is TGFβ, 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 TGFβ. 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 TGFβ 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 these motifs involve cross-talk among multiple major pathways. Our model will be useful in identifying potential therapeutic targets for the suppression of EMT, invasion, and metastasis in HCC.
authors.affiliation: Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania. ssteinway@hmc.psu.edu.
authors.forename: Steven Nathaniel
authors.initials: SN
authors.lastname: Steinway
authors.affiliation: Department of Physics, Pennsylvania State University, University Park, Pennsylvania.
authors.forename: Jorge G T
authors.initials: JG
authors.lastname: Zañudo
authors.affiliation: Department of Pediatrics, Penn State College of Medicine, Hershey, Pennsylvania.
authors.forename: Wei
authors.initials: W
authors.lastname: Ding
authors.affiliation: Department of Pediatric Gastroenterology, Bon Secours St. Mary's Hospital, Richmond, Virginia.
authors.forename: Carl Bart
authors.initials: CB
authors.lastname: Rountree
authors.affiliation: University of Virginia Cancer Center, University of Virginia School of Medicine, Charlottesville, Virginia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Feith
authors.affiliation: University of Virginia Cancer Center, University of Virginia School of Medicine, Charlottesville, Virginia.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Loughran
authors.affiliation: Department of Physics, Pennsylvania State University, University Park, Pennsylvania.
authors.forename: Reka
authors.initials: R
authors.lastname: Albert
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D053263:Gene Regulatory Networks; D053823:Hedgehog Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D015533:Transcriptional Activation / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics*; D060449:Wnt Signaling Pathway / Q000235:genetics*
chemical_list: D015820:Cadherins; D053823:Hedgehog Proteins; C509239:SHH protein, human; D016212:Transforming Growth Factor beta