Signaling pathway models as biomarkers: Patient-specific simulations of JNK activity predict the survival of neuroblastoma patients

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 hypo...

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Bibliographic Details
Published in:Science signaling Vol. 8; no. 408; p. ra130
Main Authors: Fey, Dirk, Halasz, Melinda, Dreidax, Daniel, Kennedy, Sean P, Hastings, Jordan F, Rauch, Nora, Munoz, Amaya Garcia, Pilkington, Ruth, Fischer, Matthias, Westermann, Frank, Kolch, Walter, Kholodenko, Boris N, Croucher, David R
Format: Journal Article
Language:English
Published: United States 22.12.2015
Subjects:
Adolescent
Animals
Biomarkers, Tumor - metabolism
Cell Line, Tumor
Child
Child, Preschool
Disease-Free Survival
Female
Follow-Up Studies
Humans
Infant
Male
MAP Kinase Kinase 4 - metabolism
Models, Biological
N-Myc Proto-Oncogene Protein
Neoplasms, Experimental - metabolism
Neuroblastoma - metabolism
Neuroblastoma - mortality
Nuclear Proteins - metabolism
Oncogene Proteins - metabolism
Predictive Value of Tests
Signal Transduction
Survival Rate
Zebrafish - metabolism
Zebrafish Proteins - metabolism
ISSN:1937-9145, 1937-9145
Online Access:Get more information
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Summary: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.
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ISSN:1937-9145
1937-9145
DOI:10.1126/scisignal.aab0990