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

By D. Fey, M. Halasz, D. Dreidax, S. Kennedy, Jordan F Hastings, Nora Rauch, Amaya Garcia Munoz, R. Pilkington, M. Fischer, Frank Westermann and 3 more. 2015

155 citations recorded by the source corpus.

Patient-specific modeling of a cell death–promoting pathway may lead to personalized treatment strategies. Pathway activity as a biomarker Understanding signaling networks may enable prediction of disease mechanisms or responses to therapeutic strategies. Fey et al. showed that constructing a pathway that reproduces the all-or-nothing, switch-like activation of the stress-activated kinase JNK could be used to stratify neuroblastoma patients. Switch-like activation of JNK leads to cell death. By integrating patient-specific information about the abundance of the components of the JNK pathway in neuroblastoma samples into the model, the authors simulated the activity of the pathway and accurately predicted survival on the basis of the dynamic properties of the pathway. Thus, pathway activity served as a biomarker. The results also showed that alterations in the network that prevent the switch-like activation of JNK were associated with poor survival of neuroblastoma patients, thus providing potential molecular mechanisms for the inherent resistance of some of these tumors to treatment. 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.

Subfields: Cancer Research, Molecular Biology, Neurology

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