title: Signaling pathway models as biomarkers: Patient-specific simulations of JNK activity predict the survival of neuroblastoma patients.
abstract: Signaling pathways control cell fate decisions that ultimately determine the behavior of cancer cells. Therefore, the dynamics of pathway activity may contain prognostically relevant information different from that contained in the static nature of other types of biomarkers. To investigate this hypothesis, we characterized the network that regulated stress signaling by the c-Jun N-terminal kinase (JNK) pathway in neuroblastoma cells. We generated an experimentally calibrated and validated computational model of this network and used the model to extract prognostic information from neuroblastoma patient-specific simulations of JNK activation. Switch-like JNK activation mediates cell death by apoptosis. An inability to initiate switch-like JNK activation in the simulations was significantly associated with poor overall survival for patients with neuroblastoma with or without MYCN amplification, indicating that patient-specific simulations of JNK activation could stratify patients. Furthermore, our analysis demonstrated that extracting information about a signaling pathway to develop a prognostically useful model requires understanding of not only components and disease-associated changes in the abundance or activity of the components but also how those changes affect pathway dynamics.
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Dirk
authors.initials: D
authors.lastname: Fey
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Melinda
authors.initials: M
authors.lastname: Halasz
authors.affiliation: Department of Neuroblastoma Genomics (B087), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Dreidax
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Kennedy
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
authors.forename: Jordan F
authors.initials: JF
authors.lastname: Hastings
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Nora
authors.initials: N
authors.lastname: Rauch
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Amaya Garcia
authors.initials: AG
authors.lastname: Munoz
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Ruth
authors.initials: R
authors.lastname: Pilkington
authors.affiliation: Department of Pediatric Hematology and Oncology, University Hospital Cologne, 50937 Cologne, Germany. Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany. Max Planck Institute for Metabolism Research, 50931 Cologne, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischer
authors.affiliation: Department of Neuroblastoma Genomics (B087), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Westermann
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland. School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland. Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Walter
authors.initials: W
authors.lastname: Kolch
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland. School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland. Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland. d.croucher@garvan.org.au boris.kholodenko@ucd.ie.
authors.forename: Boris N
authors.initials: BN
authors.lastname: Kholodenko
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland. The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia. St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia. d.croucher@garvan.org.au boris.kholodenko@ucd.ie.
authors.forename: David R
authors.initials: DR
authors.lastname: Croucher
mesh_terms: D000293:Adolescent; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D000071447:N-Myc Proto-Oncogene Protein; D009374:Neoplasms, Experimental / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism* / Q000401:mortality*; D009687:Nuclear Proteins / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism*; D011237:Predictive Value of Tests; D015398:Signal Transduction; D015996:Survival Rate; D015027:Zebrafish / Q000378:metabolism; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D029961:Zebrafish Proteins; D048670:MAP Kinase Kinase 4